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GPCRs` grand plans - The Stevens Lab
ANALYSIS FROM THE MAKERS OF AND DECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 THIS WEEK ANALYSIS COVER STORY 1 GPCRs’ grand plans A public-private precompetitive consortium aims to expand the number of known GPCR structures from 26 to over 200. TRANSLATIONAL NOTES 5 Merck Encycles through Canada The first disclosed grant under Merck’s 2013 initiative to fund Canadian innovation will support lead optimization of Encycle Therapeutics’ macrocycle program for IBD. 7 Incubating innovation Two years ago, Janssen formed an internal incubator to solve a key problem: managing discoveries outside its own therapeutic areas. Incubator heads recently talked with SciBX about its progress so far. TOOLS 9 Roche’s heart for diabetes Roche scientists have developed a cell-based model of diabetic cardiomyopathy, but they say it is only step one en route to a system that properly represents ventricles of a diseased heart. THE DISTILLERY 11This week in therapeutics Using IgM-based conjugates against FAIM3 for CLL; inhibiting DNM1L for Parkinson’s disease; treating inflammation-induced lung injury with maresin 1; and more… 17This week in techniques Identifying indirect interactions between proteins and small molecules; immune complex–mediated kidney disease in mice; phage-based prediction of resistance mutations; and more… INDEXES 19Company and institution index 19Target and compound index GPCRs’ grand plans By Stephen Parmley, Senior Writer In a move to expand tenfold the number of known 3D structures of the highly druggable class of GPCRs, Amgen Inc., Ono Pharmaceutical Co. Ltd. and Sanofi have teamed up with three academic organizations to create the GPCR Consortium—a precompetitive alliance to build an open-source repository of GPCR structures. The consortium could fill a hole left by the termination of the NIH-backed Protein Structure Initiative that until March constituted the main public effort to characterize GPCR structures. Raymond Stevens—who started the consortium—told SciBX in late November that Novo Nordisk A/S will also join the group. He expects to sign up another pharma before year end, and he said that the consortium hopes to reach a total of eight industry members. The academic centers involved—the iHuman Institute at ShanghaiTech University, the Shanghai Institute of Materia Medica and the University of Southern California—will conduct the research on GPCR structures and make the results and supporting data available in the public domain. Financial terms for the consortium were not disclosed. Stevens is founding director of the iHuman Institute and provost professor of biological sciences and chemistry at the University of Southern California. He is also founder of Receptos Inc. and RuiYi Inc. The goal is to elucidate the 3D structures of a large number of GPCRs and generate high-resolution pictures that can be used to explore how the receptors work and aid the design of new compounds. The consortium’s initial focus will be on diabetes, cancer and mental disorders based on the industry members’ input. But, according to Stevens, there is no limit on therapeutic areas, and new consortium members may have different interests. Stevens said that with 8 companies on board, the consortium believes it will be able to study at least 200 GPCRs. Michael Hanson, president of the GPCR Consortium, noted that GPCRs constitute the largest family of proteins in the human body and represent therapeutic targets for about 40% of marketed drugs. “What is surprising is that these developed drugs really only target a handful of the known family of GPCRs. So there is a vast untapped potential out there,” he said. But “at the moment, we only have structures for 26 of the 826 known human GPCRs. There is a lot that we do not know about this family.” (See Figure 1, “Solving a family problem.”) Hanson is the former director of structural biology at Receptos. He said that industry members will provide the consortium with libraries of their chemical compounds, many of which have fallen by 1 COVER STORY ANALYSIS EDITORIAL Editor-in-Chief: Karen Bernstein, Ph.D. Executive Editor: C. Simone Fishburn, Ph.D. Associate Editor: Michael J. Haas Senior Writers: Benjamin Boettner, Ph.D.; Kai-Jye Lou; Stephen Parmley, Ph.D. Staff Writer: Lauren Martz Research Director: Walter Yang Research Manager: Kevin Lehnbeuter Production Editors: Brandy Cafarella; Carol Evangelista; Jennifer Gustavson Copy Editor: Nicole DeGennaro Data Specialist: Mark Zipkin Design: Claudia Bentley; Miles Davies For inquiries, contact editorial@scibx.com PUBLISHING Publisher: James Butcher, Ph.D. Associate Publisher: Eric Pierce Marketing: Sara Girard; Greg Monteforte Technology: Julia Kulikova Sales: Ron Rabinowitz; Dean Sanderson; Tim Tulloch OFFICES BioCentury Publications, Inc. Nature Publishing Group San Francisco PO Box 1246 San Carlos, CA 94070-1246 T: +1 650 595 5333 New York 75 Varick Street, 9th Floor New York, NY 10013-1917 T: +1 212 726 9200 Chicago 20 N. 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He added accessing and generating that the compounds are great compounds that are going tools for binding receptors to bind to the receptors and st abi l i z i ng t he m for and analyzing the data cr ystallization and might associated with that binding be useful for bootstrapping structures to develop new event is probably the most drugs. important aspect of what “Hav i ng t h e i r h e lp i n pharma is bringing to the accessing and generat ing collaboration.” compounds that are going —Michael Hanson, to bind to the receptors and GPCR Consortium analyzing the data associated with that binding event is probably the most important aspect of what pharma is bringing to the collaboration,” he said. Lessons learned Stevens told SciBX that a major stimulus for the new collaboration was the termination of funding for the Protein Structure Initiative (PSI) by the NIH’s National Institute of General Medical Sciences earlier this year. According to an NIH press release, the initiative was discontinued after an external review committee concluded that, despite the gains made since PSI was founded in 2000, the resources, products and results were “underutilized by the broader scientific community.” PSI was originally formed to develop and use high throughput screening systems to solve 3D atomic-level structures of proteins Tokyo Chiyoda Building 6F 2-37 Ichigayatamachi Shinjuku-ku, Tokyo 162-0843 Japan T: +81 3 3267 8751 SciBX is produced by BioCentury Publications, Inc. and Nature Publishing Group Joint Steering Committee: Karen Bernstein, Ph.D., Chairman & Editor-in-Chief, BioCentury; David Flores, President & CEO, BioCentury; Bennet Weintraub, Finance Director, BioCentury; Steven Inchcoombe, Managing Director, Nature Publishing Group; Peter Collins, Ph.D., Publishing Director, NPG; Christoph Hesselmann, Ph.D., Chief Financial Officer, NPG. Copyright © 2014 Nature Publishing Group ALL RIGHTS RESERVED. 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To contact the editorial team at SciBX please e-mail editorial@scibx.com SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 2 COVER STORY ANALYSIS Figure 1. Solving a family problem. The GPCR Consortium aims to solve at least 200 unknown structures of GPCRs. SECRETIN (15) ADHESION GLLLP G LP2 P P222R P2R R GRM77 GRM4 GIIIPR GIP G IP P PR R GRM6 GR G R GLP1R GLP1 GLP GL G LP LLP1 P11R GCGR P GCGR GC PTHR PTHR2 P R22 R PTHR1 GLUTAMATE (15) GRM8 G GRM2 GRM3 TAS1R3 AS TAS1R1FZD1 TA TAS D GR GR RPC6 RPC RP PC PC6 P C66A C GRM G RM M5 M5 GRM1 GRM GR M1 FZD7 F FZD2 F FZD3 FRIZZLED/TAS2R (24) VIP PR PR2 R22 (24) LEC1 FZD6 The GPCR superfamily contains 826 TAS AS1 S11R S1R R R22 LEC2 TAS2R13 PACAP FZD8 CELSR2P TAS2R14 CRHR2 FZD5 TAS2R16 members, identified based on sequence CALCRL C LEC3 VIPR1 PR GABBR2 CR CRH RHR1 HR1 R1 CASR A TAS2R10 FZD10 TAS2R11 CRHR1 CELSR3 EMR2 TAS2R3 TA TAS TAS2 TAS2R AS TAS2R5 TA R5 BAI22 SCTR FZD FZ FZD4 ZD ZD4 D4 4 C CALCR R similarity of their hallmark 7 transmembrane F 9 FZD9 TAS TA TAS2 T AS A S2R S 22R R9 R9 G GPR60 BAI33 ETLL TA T AS A S2R S2 S 2R R8 R GABBR R1 GPR59 G R5 GHRHR RH CELSR1 LSR11 EMR3 TAS2 TA S22R R7 R TA T A S 2 R 4 domains. Structures of 16 GPCRs have CXC CXCR CX C XCR XC X CR3 CR SMOH H BAI1 A SMO EMR11 CXC CX XC CR CR5 R55 R CCR CC C CR CR1 C R111 R11 R 11 C CX CXCR2 XCR2 CC C CR10 C 1 0 SST SSTR SSTR3 SS S STR3 S ST STR TR3 TR T R R3 3 CD977 CCR CC C CR C R66 CXCR1 R SSTR S R1 R1 CXC XCR1 CR1 R1 already been solved by the GPCR Network SSTR SS SSTR5 SST S STR5 STR ST S TR5 TR T R55 R CX CXC CXCR4 XCR XCR4 CR R44 R GPR1111 CX C XCR6 XCR XC X CR6 CR C R6 R6 CXCR4 CCR CCR9 C CC CR CR9 C R99 R SST SS STR S TR2 TR T R2 R2 C CR7 CR C R77 R (black labels), a division of the NIH-backed GPR115 SSTR4 SSTR SST SS STR4 ST STR S TR TR4 T R44 R GP GPR G GPR8 PR PR8 PR R88 C CCRL2 GPR1166 GPR1122 GP GP GPR PR R77OP R GPR113 P CCR8 CCR CC C CR8 CR C R88 R PRL L L1 1 CXC3 C CXC C 3 3R R 1 OPRK1 O OPRL1 NT NTS TSR1 NTSR1 GPR110 OP O PRK RK RK1 K11 CCR CCR4 C CC CR4 CR C R44 R NTSR2 NTSR NTS N TSR TS SR S R Protein Structure Initiative that was terOPRM1 O OP OPRM OPR PR P R CC CC CR R1 HE66 TM7XN11 GP G P PR54 PR PR5 R554 G R54 R GPR11 114 NMU1 GALR1 GAL GALR A ALR R11 GALR22 CCBP2 C P22 NM NMU NMU1R N MU1R MU MU1 M U111R U U1R R G GHSR OPRD1 CCR CR R33 RDC1 RD RDC R DC D C11 X C P GPR97 97 PPYR11 NPY1R G GALR3 AD ADM A DM D DMR MR M R XCR1 NMU22R NM R MTLR MCHR1 minated in March. Another 10 structures AGTR1 A NPY2R R TACR33 CCR5 U UR2R MCHR2 CCR R 5 AGTRL A GT G GTRL TRL TR 1 A AGTR2 PrRP P P γ TAC3RL RL BDKRB2 CCR2 C GPR26 have been solved by other groups, 9 of TACR11 TACR2 GRP72 OR1A11 SALPR GPR15 NPFF1 BDKBR1 OR1D2 OLFACTORY (3 C CRTH2 NPY5R 388) 388 38 88 8 8) β RECEPTORS ORS HCRTR2 R2 CCKBR R OR1G1 GPR32 CCKAR R which are depicted in the dendrogram NPFF22 LTR2 LT TR2 TR2 R2 BLTR AD ADO A DOR DO ORA O RA R A1 GNRHRII HCRTR1 FPR1 MC3R C3 C3R C3 δ GPR78 OR3A11 TTRHHRR BLTR2 GPR11 GNRHR ADOR ADORA ADO AD A DORA DO DOR D OR ORA O RA R A3 ADORA ADORA2A ADORA 2A A MC5R M C RE α FPRL2 (gray labels). C5R1 C5R2 EB1 2 ADORA2B A B CMKLR1 G MC4R R GPR2 PR AVPR1A A GPR1 GP GPR GPR11 G PR11 PR1 PR P R11 R1 R 11119 119 LGR8 GPR26 1 F FPRL1 01 GP C3AP2R 62 L LGR7 GPR3 3 Y MC1R R GPCRs are divided into five major R1 R 11 GPR62 GPR6 GPR G PR62 P PR6 PR R622 AVPR188 FSHR GPR66 8 MRGD M D MC2R R AVP AVPR AVPR2 AV A VP VPR2 VPR V PR PR2 P R22 R CNR2 GPR61 GPR6 GPR G GP PR6 P PR PR61 R6 R R61 661 LHCGR BR B RS33 R OXTR R G GPR12 SRE SRE SR REB1 REB EB E B1 B1 LGR4 TSHR T families: rhodopsin, secretin, adhesion, CNR11 EDG3 EDG DG3 G MRGF F PTG PT P T TG GE GER GE ER4 R4 R NM NMBR MB MBR BR BR MRG G GPR500 HRH1 HR HRH1 HRH H H1 MRGX22 SRE SREB S SR SREB2 REB REB2 RE R EB EB2 E B22 B EDG1 EDG11 E MAS MTNR1B B L LGR6 GRP GR GRPR G RPR RP R PR PR H9963 H963 H96 H 99663 63 EDG EDG5 G5 G5 MTNR1A A SREB SR SRE REB3 R RE REB EB E B3 FF F FA F A1R A R FKSG80 PTGD DR D RS glutamate and frizzled/taste receptor type 2 EDG8 EDG6 DG G66 G HRH22 LGR5 EDN ED EDN DNRA D A PTGIR PTG PTGIR PTGI PT GIR G ETBRLP1 LP P11 HM74 GPR522 G GP EDG G2 G2 OPN44 O OP OPN PAR1 P2Y12 P2Y122 P MRGX1 EDNRB HRH3 F F2R F2 2 G P PR21 2 21 1 ETBRLP2 R RL RL1 L1 L 1 (TAS2R; T2R). HRH44 FKSG FKSG7 FKSG77 G77 G ED EDG E DG7 DG G7 RRH RR R RH RH M MRGX3 EDG EDG4 ED E DG4 DG D G44 G OP OP PN N3 N3 HT TR R R4 PN PNR MRGX4 Receptors with solved structures OP O P PN N1S N SW DRD DRD5 D DR RD RD RD5 D55 OPN1 N1LLW N1L HTR HT H TR6 TR T R6 R6 TAR1 DRD1 DRD D DR R RD RD1 D D1 1 RHO T TAR3 OPN1MW W in the dendrogram include: adenosine ADRB2 A DRB2 22 ADRB2 A DRB2 B2 B ADRB3 ADR ADRB GP PR58 T TAR5 GP GPR57 GPR G PR5 P PR PR57 R55577 R57 R ADRB1 TAR4 HTR2B R2B B HTR2B A2A receptor (ADORA2A), adrenergic HTR2C HTR2 HTR H HT TR2 TR2C T TR R2 R2C R2C 2C DRD4 HTR HT H T TR R5 R HTR2A TR2A 22A A AD ADR A DR D RA1D HTR HTR7 H T 7 DDRD3 DR DRD receptor b1 (ADRB1), ADRB2, CC chemoADR ADRA1 AD A DRA D DR RA1 RA R A11B A1 B HTR HT T TR R1A R1 R 1A ADR AD A DRA DR D RA RA1 R A11A H A DRD2 ADRA2A A A HT TR1E TR kine receptor 5 (CCR5; CD195), muscarinic CHRM1 HT HT TR R R111F F RHODOPSIN HTR HT H TR1 TR1D TR T R R1D 1D 1D A ADR AD DR D RA R A2C A C CHRM3 CHRM3 RM acetylcholine receptor M2 (CHRM2; HM2), (701) ADRA2B A HTR1B TR1B R1 HTR1B CHRM5 CHRM4 CHR CHRM3 (HM3), corticotropin-releasing RM22 CHRM2 factor receptor 1 (CRHR1; CRFR1), CXC chemokine receptor 1 (CXCR1), CXCR4 (NPY3R), dopamine D3 receptor (DRD3), glucagon receptor (GCGR), metabotropic glutamate receptor subtype 1 (mGluR1; GRM1), histamine H1 receptor (HRH1), serotonin (5-HT1B) receptor (HTR1B), HTR2B, neurotensin receptor 1 (NTSR1), opioid receptor d1 (OPRD1; DOR), k-opioid receptor (OPRK1; KOR), opiate receptor-like 1 (OPRL1), m-opioid receptor (OPRM1; MOR), protease-activated receptor 1 (PAR1), purinergic receptor P2Y G protein–coupled 12 (P2RY12; P2Y12), rhodopsin (RHO; OPN2), smoothened (SMO), sphingosine 1-phosphate receptor 1 (S1PR1; S1P1; EDG1). Not shown: free fatty acid receptor 1 (FFAR1; GPR40). (Figure adapted from Figure 1 in ref. 2.) 2A R AF 3 PTPR10 G R RG Katya Kadyshevskaya, The Scripps Research Institute. GP GPR R1 87 0 CY 6 S F R6 G CY LT22RL F2R G2 5 PR1S7 LT1 3 L2 A GP OGR R4 1 5 Y9 R5 P2 GP R35 Y5 GP92 P2 R GP Y10 G79 GPR91 80 P2FKS Y1 GPR 2 P2 P2Y6 P2Y P2Y4 R2 GE PT R3 A2R GE R1 BX PT GE T TGFR P PT and make them easily obtainable by the scientific community. The program involved multicenter collaborative studies and produced more than 6,300 protein structures and 400 technologies and methods to streamline the process of structure determination. Stevens was the principal investigator from The Scripps Research Institute who formed the GPCR Network, a collaborative program funded by PSI to understand GPCR structure and function. He told SciBX that the GPCR structures obtained in the PSI program were viewed as useful but the PSI program was controversial because it was less hypothesis-driven research than the National Institute of General Medical Sciences is currently funding. He added that for some of the leading academic groups in the field of GPCR structural biology research, the only solution to the cut in PSI funding was to work more closely with industry. By allowing the pharmas to select the targets and collaborate on the science, the consortium hopes to generate data that is more therapeutically useful, he told SciBX. In putting together the GPCR Consortium, Stevens used the setup of the Structural Genomics Consortium (SGC) as a template with assistance from Aled Edwards, director and CEO of the SGC. “That model worked really well, particularly for kinases and epigenetics,” said Stevens. “Before, labs were solving structures of a few kinases here and there, but the SGC did it in an organized fashion and did an incredible job of opening up the kinase knowledge base.” The SGC is a public-private partnership founded in 2004 to determine protein structures that operates out of the University of Oxford and University of Toronto. Results are placed in the Protein Data Bank, which is the primary public source of protein structures.1 The GPCR Consortium will also deposit its data in the Protein Data Bank. Like the SGC, the GPCR Consortium will rely on international collaboration between academic centers that have different strengths and skill sets. Stevens said, “In terms of novel technologies, in China we will be doing a lot of the in vitro stability screening and signaling assays, and in the U.S. we have access to a new technology called the free electron laser that is able to use much smaller crystals.” He also noted that the technology to obtain protein structures has advanced significantly in the last decade, which has lowered the cost and shortened the time it takes to generate structural data. SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 3 COVER STORY ANALYSIS Hanson added that acquiring the data is just the first step. Industry funding would also be used for organizing and sharing the data so that it can be used more effectively by the pharma partners and the larger biomedical community, he said. The importance of data management was a lesson learned from the genomics field, which also dealt with vast amounts of data, he said. “It’s very analogous to the Human Genome Project, where academia had their effort and industry had their effort,” which led to a lot of expense, inefficiency and a cottage industry of small labs engaged in redundant efforts. “What we are trying to do is take it a step further and evolve, so instead of competing we are working together to collect this information,” Stevens said. “There are a lot of GPCR data being generated, including but not limited to structural data, novel signaling pathways, allosteric modulation and polypharmacology,” he said. “We are developing solutions to integrate access and ultimately utilize all of this data to accelerate the process of drug discovery.” Parmley, S. SciBX 7(46); doi:10.1038/scibx.2014.1337 Published online Dec. 4, 2014 REFERENCES 1. Cain, C. SciBX 4(20); doi:10.1038/scibx.2011.562 2. Katritch, V. et al. Annu. Rev. Pharmacol. Toxicol. 53, 531–556 (2013) COMPANIES AND INSTITUTIONS MENTIONED Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif. GPCR Consortium, Los Angeles, Calif. National Institute of General Medical Sciences, Bethesda, Md. National Institutes of Health, Bethesda, Md. Novo Nordisk A/S (CSE:NVO; NYSE:NVO), Bagsvaerd, Denmark Ono Pharmaceutical Co. Ltd. (Tokyo:4528), Osaka, Japan Receptos Inc. (NASDAQ:RCPT), San Diego, Calif. RuiYi Inc., La Jolla, Calif. Sanofi (Euronext:SAN; NYSE:SNY), Paris, France The Scripps Research Institute, La Jolla, Calif. Shanghai Institute of Materia Medica, Shanghai, China ShanghaiTech University, Shanghai, China Structural Genomics Consortium, Oxford, U.K. University of Oxford, Oxford, U.K. University of Southern California, Los Angeles, Calif. University of Toronto, Toronto, Ontario, Canada SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 4 ANALYSIS Merck Encycles through Canada TRANSLATIONAL NOTES money the Encycle project will receive but said the deal gives IRICoR an equity stake in Encycle and increases MaRS Innovation’s existing stake. Macrocircular arguments Encycle’s macrocycle platform includes three features not found together in By Michael J. Haas, Associate Editor other macrocycle platforms: a lack of sulfur to enhance metabolic stability; inclusion of several intramolecular hydrogen bonds that alter the molecules’ The first disclosed grant under Merck & Co. Inc.’s Canadian translational folding and increase their ability to permeate cell membranes; and an upper initiative will bolster the ability of macrocycle-based Encycle size limit of three to five amino acids, which gives the molecules better oral Therapeutics Inc. to conduct lead optimization of its integrin a4b7 availability than larger rings typically achieve.3 inhibitors for inflammatory bowel disease. According to Coull, this combination of features gives the molecules— Last year, Merck launched the initiative with a C$4 million ($3.5 which Encycle has dubbed ‘nacellins’, a reference to their boat (nacelle)million) fund to support—and give a first look at—research from early stage like conformation—longer in vivo half-lives than sulfur-containing companies and academic institutes across the country. macrocycles and greater cell penetration than macrocycles that have fewer The announced deal will help finance a joint team from Encycle and intramolecular hydrogen-bonding motifs. the Institute for Research in Immunology and Cancer (IRIC) to perform The most advanced macrocycle in development is Polyphor Ltd.’s medicinal chemistry and preclinical efficacy studies. IRIC is a translational POL6326, a conformationally constrained peptide that antagonizes CXC unit housed at the University of Montreal. chemokine receptor 4 (CXCR4; NPY3R). The compound is in Phase II Encycle is a spinout from the University of Toronto founded in 2012 to testing to treat multiple myeloma (MM) using autologous transplantation solve the primary challenges of macrocycle drugs—poor cell penetration of hematopoietic stem cells. At least seven other companies have and low oral availability.1,2 macrocycles or conformationally restrained peptides or peptidomimetics According to Parimal Nathwani, the company was selected by in development to treat a range of diseases. MaRS Innovation and IRICoR (Institute Encycle’s lead nacellin program inhibits for Research in Immunology and Cancer— integrin a 4 b 7 , a protein expressed by “IRIC scientists have strong Commercialization of Research), two of the lymphocytes that binds mucosal vascular expertise in medicinal three agencies originally tasked with disbursement a d d re s s i n c e l l a d h e s i on m ol e c u l e 1 chemistry and have worked and management of the Merck fund, because it (MAdCAM-1) on endothelial cells. The with industry on optimization, was a good match with IRIC’s competencies. The interaction drives proinflammatory cells pharmacokinetics, toxicity third agency, The Centre for Drug Research to leave the circulation for the gut, which and other preclinical and Development, is not involved in this deal. contributes to the chronic inflammation in studies, so they can provide IRICoR is the commercialization arm of IRIC. IBD. Encycle with pharma-grade “Encycle has a good chemistry platform This fall, Encycle’s collaborators at Roswell optimization.” and nice early discover y work on its Park Cancer Institute completed studies of —Parimal Nathwani, integrin a4b7 inhibitor program, which is now at one of the anti–integrin a4b7 nacellins, ET-377, MaRS Innovation the point where it needs to move through lead in a mouse model of colitis that tested the optimization,” said Nathwani. “IRIC scientists ability of the compound to block movement of have strong expertise in medicinal chemistry and have worked with lymphocytes out of the plasma. industry on optimization, pharmacokinetics, toxicity and other preclinical “We got some very interesting data from the study and saw good studies, so they can provide Encycle with pharma-grade optimization.” efficacy for the compound” in this model, Coull told SciBX. He said Nathwani is VP of life sciences at MaRS Innovation, a translational that ET-377 produced results in the model comparable to those for center that commercializes discoveries from 16 academic institutions and two antibodies—an anti–mouse integrin a4b7 mAb and an anti–mouse hospitals in Ontario, including the University of Toronto. Madcam-1 mAb—when it was run in a head-to-head comparison. Encycle president and CEO Jeffrey Coull told SciBX, “We initiated In its second nacellin program, Encycle is using its macrocycle lead optimization of our integrin a4b7 inhibitors a few months ago and so technology to tackle hard-to-reach proteins involved in ubiquitination. far have identified some compounds with good potency and membrane “Pharma has been going after E3 ubiquitin ligases for years without permeability to demonstrate that our program has strong potential.” success,” Coull said, “but it’s been a tough nut to crack because the He said that the funds from Merck—combined with an equal financial protein-protein interactions involved are intracellular. We thought we contribution from Encycle—will allow his company to create “an integrated could make a nacellin large enough to interrupt SMURF’s interactions optimization team” that will conduct additional medicinal chemistry and with other proteins but small enough to get inside the cell.” in vivo studies. SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) and He added, “For us, it’s all about bandwidth. IRIC adds to the expertise SMURF2—targets of Encycle’s program—are important regulators in we already have in-house and will accelerate our efforts and get us across the focal adhesion dynamics in cancer and fibrosis. the finish line with a lead development candidate.” Coull said that Encycle has made active cell-permeable inhibitors MaRS Innovation and IRICoR will manage the Merck funds for the of SMURF1 and SMURF2. Because good membrane permeability is an joint Encycle-IRIC research team. Nathwani declined to disclose how much important advantage for nacellins, Encycle collaborated with a biochemist SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 5 ANALYSIS from the University of Toronto to develop an algorithm for predicting membrane permeability. Coull said that the algorithm uses seven different physical properties of nacellins. “The algorithm gives us a global understanding of how nacellins get through cell membranes and bind their targets, and we are actively employing it in lead optimization for both of our programs,” he told SciBX. Encycle has also completed a project funded by CQDM to generate a target-agnostic library of 1,500 nacellins. Each of the four pharma partners involved in the project—AstraZeneca plc, GlaxoSmithKline plc, Merck and Pfizer Inc.—has the right to screen the library against two targets of its choice. Coull expects the screenings to begin in about a month. CQDM, formerly the Quebec Consortium for Drug Discovery, receives funding from the federal and provincial governments, eight pharma sponsors and other partners to support the development of precompetitive research tools and technologies. Encycle has raised C$2.5 million ($2.2 million) in seed funding, most of which comes from MaRS Innovation. The company is also raising C$10–15 million ($8.8–13.1 million) in a series A round to fund the integrin a 4b 7 program through Phase II trials. Encycle expects to close the round in 1H15. Nathwani said that MaRS Innovation is putting together two other medicinal chemistry programs with IRICoR that would be funded by the Merck grant and expects to announce those programs in 1Q15. TRANSLATIONAL NOTES Steven Klein, IRICoR’s VP of business development, told SciBX that funds from the Merck initiative have also gone to two other projects that are jointly managed by IRICoR and the Centre for Drug Research and Development, but the details of those projects are undisclosed. Haas, M.J. SciBX 7(46); doi:10.1038/scibx.2014.1338 Published online Dec. 4, 2014 REFERENCES 1. Kotz, J. SciBX 5(45); doi:10.1038/scibx.2012.1176 2. Cain, C. BioCentury 20(38) A7–A13 (2012); Sept. 17, 2012 3. Haas, M.J. BioCentury 13; Aug. 4, 2014 COMPANIES AND INSTITUTIONS MENTIONED AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K. The Centre for Drug Research and Development, Vancouver, British Columbia, Canada CQDM, Montreal, Quebec, Canada Encycle Therapeutics Inc., Toronto, Ontario, Canada GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada Institute for Research in Immunology and Cancer— Commercialization of Research, Montreal, Quebec, Canada MaRS Innovation, Toronto, Ontario, Canada Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J. Pfizer Inc. (NYSE:PFE), New York, N.Y. Polyphor Ltd., Allschwil, Switzerland Roswell Park Cancer Institute, Buffalo, N.Y. University of Montreal, Montreal, Quebec, Canada University of Toronto, Toronto, Ontario, Canada SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 6 ANALYSIS TRANSLATIONAL NOTES Incubating innovation SciBX: Are there aspects of the venture world that you’ve adopted? Or perhaps changed? RW: We are certainly adopting a lot of the operating models that external venture-backed startups use, not the least of which is focused By Steve Edelson, Executive Editor of New Media teams and milestone funding. One of the big advantages a company like Janssen has in pursuing this is that if we have scientists with great Two years ago, the Janssen R&D LLC unit of Johnson & Johnson formed ideas, we can get started up quickly versus external newco and/or an internal incubator to solve a key problem: managing discoveries that capital formation. relate to diseases outside its areas of focus. Now, the incubator is lifting We’re also able to use the breadth of resources at the company. the veil on six of its programs—the most advanced of which involves a The key to creating internal entrepreneurs is to figure out how to do new approach to study autism spectrum disorder—and on its culture of it in a way where other processes in place to support more mature internal entrepreneurship. business don’t get in the way. Thus, the venture leaders have freedom Programs eligible for the incubator fall outside the set of diseases to make decisions. They have governance boards that oversee them on contained in Janssen’s five therapeutic areas of focus: cardiovascular a quarterly basis, but the leaders have freedom to work internally and disease and metabolism, immunology, infectious diseases and vaccines, externally to move projects along. neuroscience and cancer. For example, the autism spectrum disorder (ASD) incubator project SciBX: Let’s talk about some of the projects, starting with autism. is clearly under the umbrella of neuroscience, but ASD itself is not a What are the main challenges in that disease? Is it finding targets or disease of focus for Janssen. validating them? SciBX sat down with the leadership of the incubator to discuss the initiatives. The Gahan Pandina: Autism is quite complex. “The key to creating internal interview with Robert Willenbucher, Sanjay The main concern is it’s a heterogeneous entrepreneurs is to figure out Mistry and Gahan Pandina showed how disorder. In the past 5–7 years there has been how to do it in a way where Janssen’s model is similar to that of a VC firm— a massive effort to look at large populations other processes in place to taking a discovery and financing it to a specific to determine what the genetic causes might support more mature business milestone. be, and that has led to some novel thinking don’t get in the way.” Willenbucher is head of the Janssen about treatments. —Robert Willenbucher, incubator and head of cell therapy at Janssen. We know that behavioral treatments can Johnson & Johnson Mistry and Pandina are senior directors and be effective in improving symptoms and venture leads at the incubator. outcomes. But if you change behavior and Excerpts from SciBX’s conversation with the Janssen executives change biology, we think you can really improve outcomes. There follow. should be biological targets that are tractable that can help us improve on behavioral outcomes as part of that milieu of care. SciBX: What was the impetus for creating an internal incubator? SciBX: How do you go about deciding whether you have a good target? Robert Willenbucher: We’re looking at the incubator as a way to start up new entities within the company using a milestone-based model. It was GP: We have more targets than we can investigate. Because of the formed about two years ago as a way to explore high-value science and way the field has evolved, we don’t have the tools necessary to even product opportunities that fall outside the current focus areas in our interrogate the symptoms. The heterogeneous nature [of autism] therapeutic areas. also makes it difficult for us. On the clinical side, we don’t have good We use a venture-like model with investment criteria. We fund to outcome measures; we don’t know which proof-of-concept populations milestones and have projects that from the beginning are focused on we should pick. an exit, meaning where their next round of financing is coming from. This very good plethora of brain targets and this complexity of That money can come internally or externally, be it from private equity autism led us to really think about how we can get into this space and or strategic partners. investigate these new targets. That’s how we came up with the concept for our improved system. If we have the tools and the targets, we can SciBX: How do you make sure you’re seeing all the discoveries and assets select the best populations to proceed with clinical trials. the organization is producing? SciBX: Can you describe the system? RW: We communicate the opportunities in multiple ways, including town halls, meetings, requests for proposals in internal portals and via GP: The system has three components. The first is an electronic e-mail. The Janssen incubator is supported by the senior leadership of healthcare record for autism—detailed phenotyping of the patient. It’s Janssen. Bill Hait [global head of R&D at Janssen] helps in putting the collected and owned by the parent and by the healthcare professional word out. involved. SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 7 ANALYSIS The second is objective measures of symptoms. We know that electroencephalographs can distinguish autism patients. We also know there are specific symptoms that autism patients have that can be measured by biosensors, like social gaze. Patients don’t look at eyes and mouths and don’t measure cues. You can use eye tracking as a proxy for social impairment. From there you can build an array of biosensors that measure symptoms better than current standards, which involve just asking the parent, observing the child and having a behaviorally defined outcome. If you take the phenotype information and the biosensor information and pull in our third component, which is a research data warehouse, we can build algorithms that will help identify the right subpopulations to target. Say we have a drug that we think should be targeting excitability and that relates to repetitive behavior. We could measure outcomes specific to that using our system. SciBX: What other projects are being incubated? Sanjay Mistry: I’m leading a natural product drug discovery platform play that is coming up with [new chemical entities] based on taking known natural product starting points and employing novel chemistry. This venture was financed with three years of money, and the aim was to develop novel chemical space, which has been achieved, and to explore broadly the use of phenotypic screens, which are not currently in vogue in pharma. In some cases we’ve engaged in talks with external parties willing to share the risk for moving the assets to NME [new molecular entity]. SciBX: Are you talking about the financials involved in this? Platforms typically require lots of money—in the hundreds of millions of dollars. SM: We have a library of 1,600 compounds. It’s small. It’s an oriented approach to coming up with novelty that is actionable. SciBX: With the understanding that details are relatively scant on the TRANSLATIONAL NOTES remaining incubator projects, can you describe what else is being looked at? RW: One of the projects that we have up and running is around lupus, with two monoclonal antibody assets that are at NME stage. One is what we’d consider a best-in-class opportunity; the other would be a first in class. We’ve selected one of those to enter preclinical development. SciBX: Will you say which one? RW: No. We’re excited about the potential, but lupus is an area where we don’t have an existing franchise of downstream development expertise. It’s an example of where we are seeking strategic partners to bring that asset forward into further development. SciBX: Given that lupus is essentially a graveyard, it would seem like there’s a short list of would-be partners. RW: We have a deep expertise in immunology and immunobiology. It’s really the clinical expertise and track record in lupus that we’d be looking for. SciBX: What about the final three projects? RW: We have a program that is developing a multivalent biologic for methicillin-resistant [Staphylococcus]. We also have a pain program that’s focused on a novel target using a novel biologic platform to drug it. Our final project is really a drug discovery–enabling technology to facilitate the discovery and optimization of GPCR ligands. SciBX: Thank you for your time. Edelson, S. SciBX 7(46); doi:10.1038/scibx.2014.1339 Published online Dec. 4, 2014 COMPANIES AND INSTITUTIONS MENTIONED Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J. SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 8 ANALYSIS TOOLS Roche’s heart for diabetes Incubation in maturation medium also altered ionic conductance toward the adult phenotype. The voltage-gated sodium channel Nav1.5 (SCN5A) and sodium channel voltage-gated type II b-subunit (SCN2B) were both upregulated, and the cells showed higher sodium currents and greater cellular excitability than the immature cardiomyocytes. By Benjamin Boettner, Senior Writer The second step was to induce a diabetic phenotype in the mature cardiomyocytes. The team exposed the maturation medium–treated Building on cardiomyocytes generated from iPS cells by Cellular cells to a diabetic milieu containing glucose and two hormonal Dynamics International Inc., Roche scientists have developed a mediators of diabetic cardiomyopathy—endothelin 1 (EDN1; ET1) cell-based model of diabetic cardiomyopathy for use in discovery and cortisol. screening.1 The cells have the metabolic and physiological features of The diabetic medium caused a reduction in the frequency of patient-derived diabetic cardiomyocytes, but rather than stopping there, calcium transients in addition to gene expression and biochemical and the researchers want to extend the model to specifically recapitulate morphological changes that resembled features of heart cells in diabetic ventricular heart cells. cardiomyopathy. Diabetic cardiomyopathy develops from metabolic imbalances in Next, the team wanted to confirm the validity of the cells that had the diabetes and is the leading cause of mortality in people with type 2 diabetic phenotype by comparing them with cardiomyocytes created diabetes. Despite the significant clinical problem, there is no specific from patient fibroblasts. The researchers obtained skin cells from two treatment available for diabetic cardiomyopathy and there are few viable patients with diabetes who had widely differing clinical histories. One systems for screening new compounds because of the disease’s complex patient had a fast-progressing form of diabetic cardiomyopathy; the etiology. other had slowly progressing type 2 diabetes with no cardiovascular Although Cellular Dynamics International (CDI) and other disease. companies have created induced pluripotent stem (iPS) cell–derived After converting the fibroblasts to iPS cells, the team incubated cardiomyocytes that have been used in toxicity screening, the cells the patient-derived cells in maturation medium. They found that are limited in their use for this disease as cardiomyocytes derived from the patient with they show a neonatal phenotype that has fast-progressing diabetic cardiomyopathy “This study is a breakthrough different structural, molecular and metabolic had a more severely affected morphology as it represents one of the ch ar a c te r i s t i c s t h an m atu re d i ab e t i c than the cardiomyocytes developed from first demonstrations of a cardiomyocytes. For example, whereas iPS the CDI cells—but otherwise both types had polygenetic disease like cell–derived cardiomyocytes create energy similar features. Cardiomyocytes derived diabetes phenotypically by glycolysis, adult cardiomyocytes rely from the patient with slow-progressing correlating to a disease in a largely on fatty acids as an energy source, and diabetes showed an intermediate phenotype, dish.” diabetic cardiomyocytes have an even greater suggesting that the graded in vitro phenotype —Kyle Kolaja, dependency on fatty acids. reflected the disease severity in patients. Cellular Dynamics International Inc. Roberto Iacone, head of the stem cell Finally, the team tested the diabetic group in Roche’s Pharma Research and Early cardiomyocytes as a drug screening platform, Development (pRED) unit, thought the iPS cell–derived cardiomyocytes using levels of actinin-a, secretion of B-type natriuretic peptide could be a starting point to develop a model of diabetic heart cells for (BNP; NPPB) and the size of the cell nucleus as endpoints. Out of 480 screening compounds in drug discovery. Using a series of steps to create compounds, 28 dose-dependently improved these diabetic outcome cells that looked and behaved like cells from a diabetic heart, the team measures. developed a screening tool to select compounds that reduce biochemical Fluspirilene, a generic voltage-gated calcium channel inhibitor, and morphological markers of diabetes. and thapsigargin, which depletes intracellular calcium stores, were the most effective compounds in the screening assay. In addition, the Growing diabetic pilot screen identified potassium channel blockers, kinase inhibitors, The Roche team started by developing a method to mature the phosphodiesterase-5 (PDE-5) inhibitors and modulators of protein CDI-sourced cells toward a more adult-like phenotype, focusing in homeostasis as hits. The most potent compounds were also effective particular on cellular contractility as a differentiating hallmark of adult against the patient-derived cardiomyocytes. cardiomyocytes. The findings were published in Cell Reports. The team cultured cells from CDI in a maturation medium that Iacone told SciBX that the published screen served as proof of contained insulin and fatty acids and selected clones that had markedly concept but that at this point Roche is not following up on any of the elevated expression of the contractility marker actinin-a, which is an hits. Instead, the team is exploring ways to improve the maturation indicator of mature sarcomeric integrity. modalities to create diabetic cardiomyocytes, with an emphasis on cells The selected clones had higher levels of several contractile markers with ventricular cell properties. than immature cells, including myosin light chain 2 (MYL2), MYL3, He also said that Roche wants to test the maturation approach MYL4 and ATPase Ca++ transporting cardiac muscle slow twitch 2 in other disease areas, including diabetic retinopathy and macular (ATP2A2; SERCA2A). degeneration. SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 9 TOOLS ANALYSIS No need to know Kyle Kolaja, VP of business development at CDI and a coauthor of the Cell Reports paper, said, “This study is a breakthrough as it represents one of the first demonstrations of a polygenetic disease like diabetes phenotypically correlating to a disease in a dish.” According to Kolaja, one of the strengths of the system is that the use of a phenotypic screen avoids the need to fully understand the disease mechanisms and could lead to the discovery of molecules that help elucidate those mechanisms. “These phenotypic screens are a good counterbalance to isolated, overexpressed, target-based screening that pharma has used extensively,” he said. Joseph Wu told SciBX that adding genetic diversity to the platform would enhance its relevance for drug discovery. “The screening efforts can be expanded to include more cell lines from various patients to obtain a broader and more accurate response,” he said. “This would allow correlation between human genetic diversity against responses toward certain drugs, which is beneficial for the design of subsequent clinical trials.” Wu is director of the Stanford Cardiovascular Institute and a professor in the departments of medicine and radiology at the Stanford University School of Medicine. He is also cofounder and director of Stem Cell Theranostics Inc., a startup developing patient-derived iPS cells to predict cardiotoxicity and cardiovascular drug efficacy. Gary Lopaschuk thought that the team should also develop in-depth metabolic readouts, and he pointed out that the phenotypic assessment was heavily focused on the contractile properties of diabetic cardiomyocytes. For example, he said that the energetics of the cells still need to be more thoroughly investigated. “It would be very important to know whether the myocytes are truly diabetic,” he said. “Changes in mitochondrial fatty acid oxidation and activities in the responsible enzymes during culturing and drug treatments warrant a much closer investigation to make that point.” Lopaschuk is a professor of pediatrics at the University of Alberta and scientific director of the university’s Mazankowski Alberta Heart Institute and president and CEO of Metabolic Modulators Research Ltd. Iacone confirmed that adding more patient-specific diabetic cardiomyocytes to the panel is one of the team’s next steps and agreed that using molecular phenotypes would add granularity to the screening system and provide more detailed information. He said that the team is planning to use RNA sequencing to establish signatures that differ between diseased and normal heart cells. However, Iacone and Wu both believe the next major hurdle is to develop cellular models of ventricular cells in diabetic hearts. According to Iacone, the mature diabetic cardiomyocytes currently lack the identity of cardiomyocytes in human heart ventricles. Therefore, he said, “more sophisticated 3D culture models will have to mimic complex interactions between diabetic cardiomyocytes with endothelial cells and fibroblasts.” Iacone added, “Making these models will be a major focus over the next four years.” Roche declined to disclose the patent status of the diabetic cardiomyocyte platform and said that it is not available for licensing. Boettner, B. SciBX 7(46); doi:10.1038/scibx.2014.1340 Published online Dec. 4, 2014 REFERENCES 1. Drawnel, F.M. et al. Cell Rep.; published online Oct. 30, 2014; doi:10.1016/j.celrep.2014.09.055 Contact: Roberto Iacone, Roche Pharma Research and Early Development, Basel, Switzerland e-mail: roberto.iacone@roche.com COMPANIES AND INSTITUTIONS MENTIONED Cellular Dynamics International Inc. (NASDAQ:ICEL), Madison, Wis. Metabolic Modulators Research Ltd., Edmonton, Alberta, Canada Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland Stanford University School of Medicine, Stanford, Calf. Stem Cell Theranostics Inc., Palo Alto, Calif. University of Alberta, Edmonton, Alberta, Canada SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 10 THE DISTILLERY This week in therapeutics THE DISTILLERY brings you this week’s most essential scientific findings in therapeutics, distilled by SciBX editors from a weekly review of more than 400 papers in 41 of the highest-impact journals in the fields of biotechnology, the life sciences and chemistry. The Distillery goes beyond the abstracts to explain the commercial relevance of featured research, including licensing status and companies working in the field, where applicable. This week in therapeutics includes important research findings on targets and compounds, grouped first by disease class and then alphabetically by indication. Indication Target/marker/ pathway Summary Licensing status Publication and contact information Autoimmune disease Psoriasis IL-23 In vitro and mouse studies suggest an alphabody scaffold protein with high affinity for IL-23 could help treat psoriasis. In vitro, affinity-matured hits from a library screen of alphabodies bound IL-23 with subnanomolar affinity. In a mouse model of psoriasis, the lead antiIL-23 alphabody decreased human IL-23-induced skin inflammation compared with saline. Next steps include clinical development of the lead anti-IL-23 alphabody in autoimmune diseases and feasibility testing of oral delivery. Complix N.V.’s anti-IL-23 alphabody clinical candidate is in preclinical development. Bristol-Myers Squibb Co. and Johnson & Johnson market the anti-IL-23 antibody Stelara ustekinumab to treat psoriasis. At least 15 companies have anti-IL-23 therapies in Phase III or earlier testing to treat various autoimmune indications, including psoriasis. Patents issued and pending; available for partnering Desmet, J. et al. Nat. Commun.; published online Oct. 30, 2014; doi:10.1038/ncomms6237 Contact: Savvas N. Savvides, Ghent University, Ghent, Belgium e-mail: savvas.savvides@ugent.be Contact: Johan Desmet, Complix N.V., Ghent, Belgium e-mail: johan.desmet@complix.com Patent status undisclosed; unavailable for licensing Stuckey, D.W. et al. Stem Cells; published online Oct. 24, 2014; doi:10.1002/stem.1874 Contact: Khalid Shah, Massachusetts General Hospital, Boston, Mass. e-mail: kshah@mgh.harvard.edu SciBX 7(46); doi:10.1038/scibx.2014.1341 Published online Dec. 4, 2014 Cancer Brain cancer Pseudomonas aeruginosa exotoxin; IL-13 receptor a2 (IL-13RA2; IL-13R; CD213A2) Engineered P. aeruginosa exotoxin–producing neural stem cells could help treat glioblastoma multiforme (GBM). Human neural stem cells were engineered to be resistant to the exotoxin and to produce and secrete an IL13-exotoxin fusion protein (IL13-PE) that binds IL‐13RA2, a receptor expressed by GBM but not normal brain cells. In primary GBM cell lines, coculture with IL13-PE-producing neural stem cells decreased viability compared with coculture using unmodified neural stem cells. In a mouse model of resected GBM, injection of the IL13-PE-producing neural stem cells into the resection cavity decreased the residual GBM tumor volume and increased survival compared with injection of cell-free IL13-PE fusion protein. Next steps include discussions with the FDA to plan a clinical trial. SciBX 7(46); doi:10.1038/scibx.2014.1342 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 11 THE DISTILLERY This week in therapeutics (continued) Indication Breast cancer Target/marker/ pathway Inhibitor of k-light polypeptide gene enhancer in B cells kinase-e (IKBKE; IKKe); Janus kinase (JAK) Summary In vitro and mouse studies suggest inhibiting IKBKE could help treat a subset of triple-negative breast cancers (TNBCs). In a panel of IKBKE-overexpressing TNBC cell lines, the JAK and IKBKE inhibitor momelotinib decreased cell viability compared with the JAK inhibitor ruxolitinib or vehicle. In mice bearing TNBC xenograft tumors, momelotinib decreased tumor growth compared with vehicle, and momelotinib plus the MEK inhibitor Mekinist decreased tumor growth compared with either agent alone. Next steps include testing the combination of momelotinib and Mekinist in patients with TNBC. Gilead Sciences Inc. has momelotinib (CYT387), an inhibitor of JAK-1 and JAK-2, in Phase III testing to treat myeloproliferative disorder and Phase II trials to treat pancreatic cancer. Japan Tobacco Inc. and GlaxoSmithKline plc market Mekinist trametinib to treat melanoma. Incyte Corp. and Novartis AG market Jakavi/Jakafi ruxolitinib, an inhibitor of JAK-1 and JAK-2, to treat myeloproliferative disorder and have the compound in Phase II to Phase III testing to treat a range of cancers. Licensing status Findings unpatented; licensing status not applicable Publication and contact information Barbie, T.U. et al. J. Clin. Invest.; published online Nov. 3, 2014; doi:10.1172/JCI75661 Contact: William E. Gillanders, Washington University in St. Louis, St. Louis, Mo. e-mail: gillandersw@wudosis.wustl.edu Contact: David A. Barbie, Broad Institute of MIT and Harvard, Cambridge, Mass. e-mail: dbarbie@partners.org Contact: William C. Hahn, same affiliation as above e-mail: william_hahn@dfci.harvard.edu SciBX 7(46); doi:10.1038/scibx.2014.1343 Published online Dec. 4, 2014 Cancer Toll-like receptor 4 (TLR4); high mobility group box 1 (HMGB1) In vitro and mouse studies suggest inhibiting TLR4 or its ligand HMGB1 could help prevent metastasis. In a mouse model of melanoma, Tlr4 knockout decreased platelet activation, levels of circulating Hmgb1 and the number of lung metastases compared with wild-type Tlr4 expression. In cocultures of mouse platelets and mouse melanoma or Lewis lung carcinoma (LLC) cell lines, Tlr4 knockout on platelets or an antibody against HMGB1 secreted by tumor cells decreased platelet–tumor cell adhesion compared with no alteration or an inactive control antibody. In the mouse model of melanoma, the anti-HMGB1 antibody decreased lung metastases compared with the control antibody. Next steps include testing anti-HMGB1 antibodies in animals bearing human xenograft tumors. VBL Therapeutics Ltd. has VB-201, a TLR4 antagonist, in Phase II testing to treat atherosclerosis, psoriasis and inflammatory bowel disease (IBD). Unpatented; Yu, L.-X. et al. Nat. Commun.; published licensing status online Oct. 28, 2014; not applicable doi:10.1038/ncomms6256 Contact: Hong-Yang Wang, Second Military Medical University, Shanghai, China e-mail: hywangk@vip.sina.com Contact: He-Xin Yan, same affiliation as above e-mail: hexinyw@163.com SciBX 7(46); doi:10.1038/scibx.2014.1344 Published online Dec. 4, 2014 Cancer V-set domain containing T cell activation inhibitor 1 (B7-H4; VTCN1) Studies in mice and patient samples suggest antibodies against B7-H4 could help treat cancer. In staining studies on patient tumor tissues, anti-B7-H4 mAbs bound to antigen in ten different cancer types. In vitro, an antiB7-H4 mAb killed cancer cells via antibody-dependent cellular cytotoxicity and neutralized B7-H4-mediated immunosuppression. In a mouse model of B7-H4expressing colon cancer, an anti-B7-H4 mAb increased survival compared with a control IgG. Next steps include exploring mechanisms of anti-B7-H4 immunotherapy in different cancer types and evaluating combination therapy strategies. Patent application filed; licensing status undisclosed Jeon, H. et al. Cell Rep.; published online Oct. 30, 2014; doi:10.1016/j.celrep.2014.09.053 Contact: Xingxing Zang, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. e-mail: xing-xing.zang@einstein.yu.edu Contact: Steven C. Almo, same affiliation as above e-mail: steve.almo@einstein.yu.edu SciBX 7(46); doi:10.1038/scibx.2014.1345 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 12 THE DISTILLERY This week in therapeutics (continued) Indication Chronic lymphocytic leukemia (CLL) Target/marker/ pathway Fas apoptotic inhibitory molecule 3 (FAIM3; TOSO) Summary In vitro and mouse studies suggest IgM-based conjugates targeting FAIM3 could help treat CLL. The IgM receptor FAIM3 is overexpressed on CLL cells. The conjugates consisted of two or three constant domains of human IgM linked to a cytotoxic payload. In peripheral blood mononuclear cells isolated from patients with CLL, the lead conjugate selectively killed malignant B cells, whereas the free cytotoxic payload killed both malignant B cells and normal T cells. In a mouse xenograft model of CLL, the lead conjugate decreased tumor burden compared with vehicle and had no effect on T cell numbers. Next steps include conjugating the IgM scaffold to different linkers and drugs to optimize the delivery of cytotoxic payloads. Licensing status Patent application filed; available for licensing Publication and contact information Vire, B. et al. Cancer Res.; published online Oct. 24, 2014; doi:10.1158/0008-5472.CAN-14-2030 Contact: Adrian Wiestner, National Heart, Lung, and Blood Institute, Bethesda, Md. e-mail: wiestnera@mail.nih.gov Contact: Christoph Rader, Scripps Florida, Jupiter, Fla. e-mail: crader@scripps.edu SciBX 7(46); doi:10.1038/scibx.2014.1346 Published online Dec. 4, 2014 Colorectal cancer Adenomatous polyposis coli (APC); BH3 interacting domain death agonist (BID) Studies in mice and patient samples suggest activating Unpatented; BID could help prevent colorectal cancer in patients who licensing status carry mutations in the APC tumor suppressor. In patients not applicable with colonic adenoma, NSAID use, which is known to decrease colon cancer risk, was positively associated with BID activation in the tumors. In Apc-deficient mice, homozygous knockout of Bid decreased the tumorpreventive effect of the generic NSAID sulindac and decreased survival compared with wild-type Bid expression. Next steps include studies to identify signaling events upstream of BID and develop screening assays that could identify cancer-preventing agents. Leibowitz, B. et al. Proc. Natl. Acad. Sci. USA; published online Nov. 3, 2014; doi:10.1073/pnas.1415178111 Contact: Lin Zhang, University of Pittsburgh School of Medicine, Pittsburgh, Pa. e-mail: zhanglx@upmc.edu Contact: Jian Yu, same affiliation as above e-mail: yuj2@upmc.edu SciBX 7(46); doi:10.1038/scibx.2014.1347 Published online Dec. 4, 2014 Cutaneous T Killer cell cell lymphoma immunoglobulin(CTCL) like receptor three domains long cytoplasmic tail 2 (KIR3DL2; CD158K) Studies in mice and patient samples suggest an antiKIR3DL2 antibody could help treat the mycosis fungoides and Sézary syndrome subtypes of CTCL, which overexpress KIR3DL2. In two mouse xenograft models of KIR3DL2+ CTCL, the anti-KIR3DL2 mAb IPH4102 decreased tumor growth and increased survival compared with an inactive control mAb. In peripheral blood monocytes from patients with Sézary syndrome, IPH4102 increased tumor cell death compared with control without affecting the viability of NK cells. Innate Pharma S.A. plans to start a Phase I trial of IPH4102 in CTCL next year. Patented by Innate Pharma; available for licensing and partnering Marie-Cardine, A. et al. Cancer Res.; published online Nov. 1, 2014; doi:10.1158/0008-5472.CAN-14-1456 Contact: Hélène Sicard, Innate Pharma S.A., Marseille, France e-mail: helene.sicard@innate-pharma.fr Contact: Anne Marie-Cardine, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France e-mail: anne.marie-cardine@inserm.fr Patented; available for licensing Hong, C. et al. Cell Metab.; published online Nov. 4, 2014; doi:10.1016/j.cmet.2014.10.001 Contact: Peter Tontonoz, University of California, Los Angeles, Calif. e-mail: ptontonoz@mednet.ucla.edu Contact: Ryan E. Temel, University of Kentucky, Lexington, Ky. e-mail: ryan.temel@uky.edu SciBX 7(46); doi:10.1038/scibx.2014.1348 Published online Dec. 4, 2014 Cardiovascular disease Atherosclerosis Myosin regulatory light chain interacting protein (MYLIP; MIR; IDOL); liver X receptor (LXR) Nonhuman primate studies suggest combining MYLIP inhibitors with LXR agonists could help treat atherosclerosis. LXR agonists used in atherosclerosis treatment raise plasma low-density lipoprotein (LDL) levels as a side effect. In normal nonhuman primates, an LXR agonist increased plasma LDL levels and hepatic Mylip mRNA levels compared with vehicle. In nonhuman primates fed a high-fat diet, an antisense oligonucleotide against MYLIP attenuated LXR agonist–induced increases in plasma LDL levels. Ongoing work includes screening for small molecule MYLIP inhibitors. Exelixis Inc. and Bristol-Myers Squibb Co. have XL041 (BMS-852927), a small molecule modulator of LXR, in Phase I testing to treat metabolic syndrome. Vitae Pharmaceuticals Inc. has two LXR-b (NR1H2) agonists in preclinical development: VTP-38443 for acute coronary syndrome and VTP-38543 for dermatitis. SciBX 7(46); doi:10.1038/scibx.2014.1349 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 13 THE DISTILLERY This week in therapeutics (continued) Indication Target/marker/ pathway Myocardial SWI/SNF related infarction (MI) matrix associated actin dependent regulator of chromatin subfamily a member 5 (SMARCA5; SNF2H); farnesyltransferase CAAX box-b (FNTB); microRNA-99 (miR-99); miR-100; microRNA let-7 (MIRLET7; LET-7) Summary Licensing status Zebrafish and mouse studies suggest upregulating Patent and SMARCA5 and FNTB could help recovery after MI. In a licensing status zebrafish cardiac injury model, regenerating cardiac tissue unavailable exhibited lower levels of mir-99, mir-100 and let-7 and higher levels of their targets, smarca5 for the miRNAs and fntb for let-7, than cardiac tissue in uninjured controls. However, cardiac levels of the miRNAs in mouse models of MI and noninfarcted control mice were comparable. In the mouse model of MI, intracardial delivery of oligonucleotides against miR-99, miR-100 and Let-7 increased Smarca5 and Fntb levels in cardiac tissues and decreased infarct volume and fibrotic scarring compared with delivery of scrambled control oligonucleotides. Next steps could include testing direct upregulation of SMARCA5 and FNTB in mammalian models of MI. Publication and contact information Aguirre, A. et al. Cell Stem Cell; published online Nov. 6, 2014; doi:10.1016/j.stem.2014.10.003 Contact: Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies, La Jolla, Calif. e-mail: belmonte@salk.edu SciBX 7(46); doi:10.1038/scibx.2014.1350 Published online Dec. 4, 2014 Endocrine/metabolic disease Diabetes Not applicable Rat studies suggest a glucosylflavonoid compound derived Patent and from the Genista tenera plant could help treat diabetes. licensing status In rat models of chemical-induced diabetes, the G. unavailable tenera–derived compound 8-b-d-glucopyranosylgenistein increased glucose tolerance and glucose-stimulated insulin secretion compared with vehicle without observable toxicity. Next steps could include testing the compound in additional diabetes models and identifying its molecular target. Jesus, A.R. et al. J. Med. Chem.; published online Oct. 27, 2014; doi:10.1021/jm501069h Contact: Amélia P. Rauter, University of Lisbon, Lisbon, Portugal e-mail: aprauter@fc.ul.pt SciBX 7(46); doi:10.1038/scibx.2014.1351 Published online Dec. 4, 2014 Infectious disease Staphylococcus S. aureus catabolite control protein E (ccpE) In vitro and mouse studies suggest activating ccpE could help treat Staphylococcus infection. In S. aureus cells, ccpE knockout increased production of the staphyloxanthin virulence factor, acquisition of iron and expression of virulence genes compared with wild-type ccpE expression. In a coculture of human blood and S. aureus, ccpE knockout increased bacterial survival. In a mouse model of S. aureus–induced abscess formation, ccpE knockout increased bacterial survival in the kidney and liver. Ongoing studies include screening for ccpE activators. Patent status not applicable; unavailable for licensing SciBX 7(46); doi:10.1038/scibx.2014.1352 Published online Dec. 4, 2014 Ding, Y. et al. Proc. Natl. Acad. Sci. USA; published online Nov. 3, 2014; doi:10.1073/pnas.1411077111 Contact: Lefu Lan, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China e-mail: llan@mail.shcnc.ac.cn Contact: Cai-Guang Yang, same affiliation as above e-mail: yangcg@simm.ac.cn Inflammation Allergy; asthma MicroRNA-19a (miR-19a) Studies in mice and patient samples suggest inhibition of Patent and miR-19a could help treat asthma. In bronchoalveolar lavage licensing status from patients with asthma, miR-19a expression was higher unavailable than that in healthy controls. In a mouse asthma model, miR-19a promoted the production of T helper type 2 cell cytokines, which are associated with disease pathology. Next steps could include testing miR-19a inhibition in additional models of allergic disease. Simpson, L.J. et al. Nat. Immunol.; published online Nov. 2, 2014; doi:10.1038/ni.3026 Contact: K. Mark Ansel, University of California, San Francisco, Calif. e-mail: mark.ansel@ucsf.edu SciBX 7(46); doi:10.1038/scibx.2014.1353 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 14 THE DISTILLERY This week in therapeutics (continued) Indication Target/marker/ pathway Summary Licensing status Publication and contact information Neurology Alzheimer’s disease (AD) MicroRNA-1883p (miR-188-3p); monoacylglycerol lipase (MAGL); b-site APP-cleaving enzyme 1 (BACE1) Studies in human samples and mice suggest miR-188-3p could help treat AD. In brain tissue from a mouse model of AD or patients with AD, miR-188-3p levels were lower than those in tissue from healthy controls. In the mouse model, inhibition of Magl—an enzyme previously shown to induce amyloidogenic Bace1—increased levels of miR188-3p and decreased levels of Bace1 in a miR-188-3pdependent manner compared with vehicle, thus identifying Bace1 as a target of the miRNA. Also in the mouse model, hippocampal delivery of miR-188-3p decreased Bace1 levels and increased synaptic transmission, cognitive function and motor function compared with a scrambled control miRNA. Next steps include developing a safe and efficient vector for delivering miR-188-3p. Provisional patent application filed; licensing status undisclosed Zhang, J. et al. J. Neurosci.; published online Nov. 5, 2014; doi:10.1523/JNEUROSCI.1165-14.2014 Contact: Chu Chen, Louisiana State University Health Sciences Center, New Orleans, La. e-mail: chen502@gmail.com or cchen@lsuhsc.edu SciBX 7(46); doi:10.1038/scibx.2014.1354 Published online Dec. 4, 2014 Alzheimer’s disease (AD) Transient receptor potential cation channel subfamily M member 2 (TRPM2); b-amyloid 40 (Ab40); poly(ADP-ribose) polymerase (PARP) In vitro and mouse studies suggest TRPM2 inhibitors Unpatented; could help treat AD. Ab40 induces pathological changes in licensing status cerebral vasculature that contribute to AD progression. In not applicable cerebral endothelial cells from mouse models of AD, Ab40 induced activation of Parp and Trpm2 and increased influx of cell-damaging Ca2+ compared with vehicle. In wild-type mice receiving cortical infusions of Ab40 and a transgenic mouse model of AD, Trpm2 knockout or TRPM2 inhibitors decreased cerebrovascular dysfunctions compared with wild-type Trpm2 expression or vehicle. Next steps include developing inhibitors that specifically target TRPM2 on endothelial cells. Park, L. et al. Nat. Commun.; published online Oct. 29, 2014; doi:10.1038/ncomms6318 Contact: Costantino Iadecola, Weill Cornell Medical College, New York, N.Y. e-mail: coi2001@med.cornell.edu SciBX 7(46); doi:10.1038/scibx.2014.1355 Published online Dec. 4, 2014 Neurology Ras/RAF/MEK/ERK pathway; Src homology protein tyrosine phosphatase 2 (SHP-2; SHPTP2; PTPN11) Mouse studies suggest inhibiting ERK activity could help Patent pending; treat cognitive deficits in Noonan syndrome, a disease available for caused by mutations in PTPN11 and other Ras/RAF/MEK/ licensing ERK pathway genes. In mice, knock-in or hippocampal delivery of Ptpn11 gain-of-function mutations led to memory and learning deficits similar to those seen in patients with Noonan syndrome and increased hippocampal ERK activity and excitatory synaptic function compared with expression of wild-type Ptpn11. In the Ptpn11-mutant mice, decreasing Erk activity with a MEK inhibitor or Altocor lovastatin, which inhibits Ras activity, decreased memory and learning deficits compared with vehicle. Next steps include clinical testing of ERK inhibition in patients with Noonan syndrome. Merck & Co. Inc. markets Altocor to treat hypercholesterolemia. Lee, Y.-S. et al. Nat. Neurosci.; published online Nov. 10, 2014; doi:10.1038/nn.3863 Contact: Alcino J. Silva, University of California, Los Angeles, Calif. e-mail: silvaa@mednet.ucla.edu Contact: Yong-Seok Lee, same affiliation as above e-mail: yongseok@cau.ac.kr SciBX 7(46); doi:10.1038/scibx.2014.1356 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 15 THE DISTILLERY This week in therapeutics (continued) Indication Target/marker/ pathway Parkinson’s disease (PD) Dynamin 1-like (DNM1L; DRP1) Summary Licensing status Mouse studies suggest inhibiting DNM1L could help Patented; treat PD. In two mouse models of established PD, striatal available for injection of an adeno-associated viral (AAV) vector licensing encoding Dnm1l that harbored a loss-of-function mutation or i.p. injection of a DNM1L inhibitor increased striatal dopamine release compared with an AAV vector encoding a control protein or vehicle injection. In a mouse model of chemical-induced PD, pretreatment with the AAV vector/ mutant Dnm1l gene therapy or DNM1L inhibitor decreased loss of dopaminergic neurons compared with pretreatment using control vector or vehicle. Ongoing work includes optimizing the gene therapy and DNM1L inhibitor and testing them in additional animal models of PD. Publication and contact information Rappold, P.M. et al. Nat. Commun.; published online Nov. 5, 2014; doi:10.1038/ncomms6244 Contact: Kim Tieu, University of Rochester School of Medicine, Rochester, N.Y. e-mail: kim.tieu@plymouth.ac.uk SciBX 7(46); doi:10.1038/scibx.2014.1357 Published online Dec. 4, 2014 Pulmonary disease Acute lung injury Maresin 1 (MaR1) In vitro and mouse studies suggest MaR1 could help protect Patent and against inflammation-induced lung injury. Maresins are licensing status a family of small molecules that mediate resolution of unavailable inflammation. In a mouse model of acute lung injury, levels of MaR1 in lung tissue were higher than preinjury baselines for up to 72 hours postinjury. In the mouse model, intravascular infusion of MaR1 one hour after injury decreased lung damage, edema, tissue hypoxia and inflammatory cell infiltration compared with vehicle. In human whole blood treated with proinflammatory factors, MaR1 decreased the formation of neutrophil-platelet aggregates that contribute to inflammation compared with vehicle. Next steps could include testing the effects of MaR1 in other models of organ injury. Abdulnour, R.-E.E. et al. Proc. Natl. Acad. Sci. USA; published online Nov. 4, 2014; doi:10.1073/pnas.1407123111 Contact: Bruce D. Levy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass. e-mail: blevy@partners.org SciBX 7(46); doi:10.1038/scibx.2014.1358 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 16 THE DISTILLERY This week in techniques THE DISTILLERY brings you this week’s most essential scientific findings in techniques, distilled by SciBX editors from a weekly review of more than 400 papers in 41 of the highest-impact journals in the fields of biotechnology, the life sciences and chemistry. The Distillery goes beyond the abstracts to explain the commercial relevance of featured research, including licensing status and companies working in the field, where applicable. This week in techniques includes findings about research tools, disease models and manufacturing processes that have the potential to enable or improve all stages of drug discovery and development. Approach Summary Publication and contact Licensing status information Assays & screens Ex vivo detection of indirect therapeutic protein–small molecule drug interactions on the liver An ex vivo method for detecting indirect effects of therapeutic Patent and proteins on liver cells could help identify protein drugs that mask licensing status toxicities of coadministered small molecule drugs. Indirect therapeutic unavailable protein–small molecule drug interactions may occur when a protein drug stimulates whole blood to secret factors that suppress drugmetabolizing liver enzymes—a common marker of drug toxicity. In culture, blood cells treated with an anti-CD28 antibody secreted higher levels of proinflammatory cytokines than a control antibody or saline. In cocultures of human hepatocytes and Kupffer cells, plasma from anti-CD28 antibody–treated whole blood suppressed three cytochrome P450 (p450) liver enzymes, whereas media containing the anti-CD28 antibody alone did not suppress these enzymes. Next steps could include testing other therapeutic proteins with the method. Czerwiński, M. et al. Drug Metab. Dispos.; published online Oct. 17, 2014; doi:10.1124/dmd.114.060186 Contact: Maciej Czerwiński, XenoTech LLC, Lenexa, Kan. e-mail: mczerwinski@xenotechllc.com SciBX 7(46); doi:10.1038/scibx.2014.1359 Published online Dec. 4, 2014 Screening for diabetic cardiomyopathy (DCM) therapies in induced pluripotent stem (iPS) cell–derived cardiomyocytes Patent status undisclosed; unavailable for licensing Drawnel, F.M. et al. Cell Rep.; published online Oct. 30, 2014; doi:10.1016/j.celrep.2014.09.055 Contact: Roberto Iacone, Roche Pharma Research and Early Development, Basel, Switzerland e-mail: roberto.iacone@roche.com Mice from the CC resource could help identify markers of sensitivity Patent and and resistance to Ebola viral infection. Existing mouse models of the licensing status disease do not recapitulate Ebola hemorrhagic fever (EHF), a hallmark unavailable of the infection in patients. When the 47 genetically diverse strains of mice that comprise the CC resource were challenged with lethal doses of a mouse-adapted strain of Ebola virus, 14 exhibited complete or partial resistance to infection while 16 exhibited EHF-induced mortality. Transcriptional analysis of hepatocytes from the mouse strains that developed EHF identified associations between mortality and alleles of tyrosine kinase receptor 2 (Tie2) that were previously linked to inflammatory coagulopathies and vascular dysfunction. Next steps could include surveying the CC mouse strains for additional genetic contributions to Ebola infection. Rasmussen, A.L. et al. Science; published online Oct. 30, 2014; doi:10.1126/science.1259595 Contact: Michael G. Katze, University of Washington, Seattle, Wash. e-mail: honey@uw.edu iPS cell–derived cardiomyocytes could be used to screen for therapies to treat DCM. The approach utilized two types of iPS cell–derived cardiomyocytes: one generated using fibroblasts taken from healthy individuals and cultured in medium designed to mimic diabetic conditions (DM-treated cells) and another generated using fibroblasts taken from patients with diabetes. Both types of cardiomyocytes exhibited loss of sarcomeric integrity and reduced calcium transients and other features of DCM. In the DM-treated cardiomyocytes, initial library screening identified several compounds that reversed the DCM phenotype, and subsequent screening of a subset of those initial hits in the patient-derived cardiomyocytes confirmed the compounds’ effects. Next steps include investigating differentiation conditions for generating cardiomyocytes that resemble ventricular cardiomyocytes of patients with diabetes (see Roche’s heart for diabetes, page 9). SciBX 7(46); doi:10.1038/scibx.2014.1360 Published online Dec. 4, 2014 Disease models Mice from the Collaborative Cross (CC) resource as models of Ebola viral infection SciBX 7(46); doi:10.1038/scibx.2014.1361 Published online Dec. 4, 2014 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 17 THE DISTILLERY This week in techniques (continued) Approach Summary Publication and contact Licensing status information Mouse model of A mouse model of immune complex–mediated kidney disease could Unpatented; immune complex– help identify new therapeutic strategies to treat the condition. Mice unlicensed mediated kidney disease deficient in IgG1 and immunized with goat antimouse IgD antiserum showed immune complex deposition predominantly containing IgG3 subtypes in the kidney and developed lethal kidney disease. In this model, an antigen-specific IgG1 prevented IgG3-driven kidney pathology compared with a control IgG1. Next steps include analysis of the role of different IgG isotypes in models of blistering skin disease. Strait, R.T. et al. Nature; published online Nov. 2, 2014; doi:10.1038/nature13868 Contact: Fred D. Finkelman, University of Cincinnati, Cincinnati, Ohio e-mail: finkelfd@ucmail.uc.edu SciBX 7(46); doi:10.1038/scibx.2014.1362 Published online Dec. 4, 2014 Drug platforms Automated, in vitro generation of specific neuronal subtypes from human pluripotent stem cells An automated, in vitro protocol for generating neuronal subtypes from Patent and human pluripotent stem cells could be useful for developing cellular licensing status therapies to treat neurological diseases. The protocol involves treating unavailable human pluripotent stem cells with four compounds—a winglesstype MMTV integration site pathway agonist, a hedgehog pathway agonist, retinoic acid and fibroblast growth factor 2 (FGF2)—to induce their differentiation into progenitors of specific neuronal subtypes, including spinal motor neurons and cranial motor neurons. In the resulting progenitor cells, treatment with a g-secretase inhibitor promoted their growth and maturation into neurons that showed markers and electrophysiological properties of the respective neuron subtype. Next steps could include extending the protocol to generate other specific human neuronal cell types. Maury, Y. et al. Nat. Biotechnol.; published online Nov. 10, 2014; doi:10.1038/nbt.3049 Contact: Stéphane Nedelec, Institut National de la Santé et de la Recherche Médicale (INSERM), Evry, France e-mail: stephane.nedelec@inserm.fr SciBX 7(46); doi:10.1038/scibx.2014.1363 Published online Dec. 4, 2014 Phage-assisted continuous evolution (PACE) to identify and predict drug-resistant protease mutations caused by protease inhibitors An in vitro method of directed evolution called PACE could help Patented; available identify and predict drug-resistant protease mutations caused by for licensing protease inhibitors. The PACE platform links the phage life cycle to the cleavage activity of an HCV protease against its polypeptide substrate in an automated, continuous-flow format. After one to three days in the presence of Sunvepra asunaprevir or danoprevir, the PACE platform evolved resistance mutations in the protease targets of each compound that are known to emerge in patients with HCV. Ongoing work includes using the platform to evolve proteases with programmed target specificities. Sunvepra, an HCV NS3 protease inhibitor from Bristol-Myers Squibb Co., is approved to treat HCV infection. Roche and Ascletis Pharmaceuticals Co. Ltd. have danoprevir, an HCV NS3/N4 protease complex inhibitor, in Phase II testing to treat HCV infection. Dickinson, B.C. et al. Nat. Commun.; published online Oct. 30, 2014; doi:10.1038/ncomms6352 Contact: David R. Liu, Harvard University, Cambridge, Mass. e-mail: drliu@fas.harvard.edu SciBX 7(46); doi:10.1038/scibx.2014.1364 Published online Dec. 4, 2014 Screening platform to produce high-affinity nanobodies A platform that uses high throughput DNA sequencing and mass Patent application spectrometric analysis of variable domains from immunized filed; licensing llamas could be used to develop high-affinity nanobody reagents status undisclosed and therapeutics. Nanobodies are camelid-derived, single-domain antibodies. In the current platform, llamas were immunized with GFP and variable domain fragments from the resulting antibodies were analyzed by mass spectrometry. In parallel, variable domain cDNAs from bone marrow lymphocytes were sequenced and computational analysis was used to identify corresponding peptides from the mass spectrometry data. After incorporating top-ranked sequences into recombinant nanobodies, several anti-GFP nanobodies were identified with affinities in the subnanomolar range. Next steps include generating nanobodies against targets with diagnostic and therapeutic utility. SciBX 7(46); doi:10.1038/scibx.2014.1365 Published online Dec. 4, 2014 Fridy, P.C. et al. Nat. Methods; published online Nov. 2, 2014; doi:10.1038/nmeth.3170 Contact: Michael P. Rout, The Rockefeller University, New York, N.Y. e-mail: rout@rockefeller.edu Contact: Brian T. Chait, same affiliation as above e-mail: chait@rockefeller.edu Contact: David Fenyö, New York University School of Medicine, New York, N.Y. e-mail: david@fenyolab.org SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 18 INDEXES Company and Institution index A Amgen Inc. Ascletis Pharmaceuticals Co. Ltd. AstraZeneca plc 1 18 6 B Bristol-Myers Squibb Co. 11,13,18 C Cellular Dynamics International Inc. 9 Centre for Drug Research and Development 5 Complix N.V. 11 CQDM 6 E Encycle Therapeutics Inc. Exelixis Inc. 5 13 F Food and Drug Administration 11 G Gilead Sciences Inc. GlaxoSmithKline plc GPCR Consortium 12 6,12 1 I Incyte Corp. Innate Pharma S.A. Institute for Research in Immunology and Cancer Institute for Research in Immunology and Cancer—Commercialization of Research 12 13 5 5 J Japan Tobacco Inc. Johnson & Johnson 12 7,11 M MaRS Innovation Merck & Co. Inc. Metabolic Modulators Research Ltd. 5 5,15 10 N National Institute of General Medical Sciences National Institutes of Health Novartis AG Novo Nordisk A/S 2 1 12 1 O Ono Pharmaceutical Co. Ltd. 1 P Pfizer Inc. Polyphor Ltd. 6 5 R Receptos Inc. 1 Roche 9,18 Roswell Park Cancer Institute 5 RuiYi Inc. 1 S Sanofi Scripps Research Institute 1 3 Shanghai Institute of Materia Medica ShanghaiTech University Stanford University School of Medicine Stem Cell Theranostics Inc. Structural Genomics Consortium 1 1 10 10 3 U University of Alberta University of Montreal University of Oxford University of Southern California University of Toronto 10 5 3 1 3,5 V VBL Therapeutics Ltd. Vitae Pharmaceuticals Inc. 12 13 Target and compound index CXCR1 CXCR4 CYT387 Cytochrome P450 D Danoprevir DNA DNM1L Dopamine D3 receptor DOR DRD3 DRP1 Dynamin 1-like E3 ubiquitin ligase EDG1 EDN1 Endothelin 1 ERK ET1 ET-377 F A FAIM3 Farnesyltransferase CAAX box-b Fas apoptotic inhibitory molecule 3 Fatty acid FFAR1 FGF2 Fibroblast growth factor 2 Fluspirilene FNTB Free fatty acid receptor 1 Frizzled 15 9 13 3 3 3 3 3 15 13 18 9 9 B b-amyloid 40 b-site APP-cleaving enzyme 1 B-type natriuretic peptide B7-H4 BACE1 BH3 interacting domain death agonist BID BMS-852927 BNP 15 15 9 12 15 13 13 13 9 C Calcium CC chemokine receptor 5 ccpE CCR5 CD158K CD195 CD213A2 CD28 CHRM2 CHRM3 Corticotropin-releasing factor receptor 1 Cortisol CRFR1 CRHR1 CXC chemokine receptor 1 CXC chemokine receptor 4 9 3 14 3 13 3 11 17 3 3 3 9 3 3 3 5 18 18 16 3 3 3 16 16 E 8-b-d-glucopyranosylgenistein 14 Ab40 Actinin-a Adenomatous polyposis coli Adenosine A2A receptor ADORA2A ADRB1 ADRB2 Adrenergic receptor b1 Altocor APC Asunaprevir ATP2A2 ATPase Ca++ transporting cardiac muscle slow twitch 2 3 3,5 12 17 5 3 9 9 15 9 5 13 14 13 9 3 18 18 9 14 3 3 IKKe IL-13 receptor a2 IL-13R IL-13RA2 IL-23 IL13-exotoxin fusion protein IL13-PE Inhibitor of k-light polypeptide gene enhancer in B cells kinase-e Insulin Integrin a4b7 IPH4102 12 11 11 11 11 11 12 14 5 13 J JAK JAK-1 JAK-2 Jakafi Jakavi Janus kinase 12 12 12 12 12 12 K k-opioid receptor 3 Killer cell immunoglobulin-like receptor three domains long cytoplasmic tail 2 13 KIR3DL2 13 KOR 3 L LDL LET-7 Liver X receptor Lovastatin Low-density lipoprotein LXR LXR-b 13 14 13 15 13 13 13 G M g-secretase 18 GCGR 3 GFP 18 Glucagon receptor 3 Glucose9,14 GPCR 1,8 GPR40 3 GRM1 3 m-opioid receptor 3 Macrocycle 5 MAdCAM-1 5 MAGL 15 MaR1 16 Maresin 16 Maresin 1 16 MEK 12,15 Mekinist 12 Metabotropic glutamate receptor subtype 1 3 Methicillin 8 mGluR1 3 MicroRNA let-7 14 MicroRNA-188-3p 15 MicroRNA-19a 14 MicroRNA-99 14 MIR 13 miR-100 14 miR-188-3p 15 miR-19a 14 miR-99 14 MIRLET7 14 Momelotinib 12 Monoacylglycerol lipase 15 MOR 3 Mucosal vascular addressin cell adhesion molecule 1 5 Muscarinic acetylcholine receptor M2 3 MYL2 9 H HCV NS3 protease HCV NS3/N4 protease complex HCV protease Hedgehog High mobility group box 1 Histamine H1 receptor HM2 HM3 HMGB1 HRH1 HTR1B HTR2B 18 18 18 18 12 3 3 3 12 3 3 3 I IDOL IgD IgG IgG1 IgG3 IgM IKBKE 13 18 12,18 18 18 13 12 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 19 INDEXES MYL3 MYL4 MYLIP Myosin light chain 2 Myosin regulatory light chain interacting protein 9 9 13 9 13 N Nacellin Nav1.5 Neurotensin receptor 1 NPPB NPY3R NR1H2 NSAID NTSR1 5 9 3 9 3,5 13 13 3 O Opiate receptor-like 1 Opioid receptor d1 OPN2 OPRD1 OPRK1 OPRL1 OPRM1 3 3 3 3 3 3 3 P P2RY12 P2Y12 p450 PAR1 PARP 3 3 17 3 15 PDE-5 9 Phosphodiesterase-5 9 POL6326 5 Poly(ADP-ribose) polymerase 15 Potassium channel 9 Protease-activated receptor 1 3 Pseudomonas aeruginosa exotoxin 11 PTPN11 15 Purinergic receptor P2Y G protein–coupled 12 3 R RAF Ras Retinoic acid RHO Rhodopsin RNA Ruxolitinib 15 15 18 3 3 10 12 S S. aureus catabolite control protein E S1P1 S1PR1 SCN2B SCN5A SERCA2A Serotonin (5-HT1B) receptor SHP-2 14 3 3 9 9 9 3 15 SHPTP2 SMAD specific E3 ubiquitin protein ligase 1 SMARCA5 SMO Smoothened SMURF1 SMURF2 SNF2H Sodium channel voltagegated type II b-subunit Sphingosine 1-phosphate receptor 1 Src homology protein tyrosine phosphatase 2 Staphyloxanthin virulence factor Stelara Sulfur Sulindac Sunvepra SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 5 15 9 Thapsigargin Tie2 TLR4 Toll-like receptor 4 TOSO Trametinib Transient receptor potential cation channel subfamily M member 2 TRPM2 Tyrosine kinase receptor 2 3 U 15 V 5 14 3 3 5 5 14 14 11 5 13 18 14 T T helper type 2 cell cytokine T2R TAS2R Taste receptor type 2 14 3 3 3 Ustekinumab V-set domain containing T cell activation inhibitor 1 VB-201 Voltage-gated calcium channel VTCN1 VTP-38443 VTP-38543 9 17 12 12 13 12 15 15 17 11 12 12 9 12 13 13 W Wingless-type MMTV integration site pathway 18 X XL041 SciBX: Science–Business eXchangeDECEMBER 4, 2014 • VOLUME 7 / NUMBER 46 13 20
