analysis

AUGUST 4, 2011 • VOLUME 4 / NUMBER 30

1

fROM ThE MAkERS Of ANd

THIS WEEKANALYSIS

COVER STORY1 Epizyme connects the DOTs Epizyme believes it has produced the first evidence for in vivo

efficacy for a histone methyltransferase inhibitor. Although the biotech thinks its animal findings have implications for an entire class of new drugs, it will aim to begin human studies in a small but aggressive subset of acute leukemias.

TARGETS & MECHANISMS4 Agios’ high metabolism Agios Pharmaceuticals and collaborators at MIT and harvard

have used an RNAi-based in vivo screening technology to identify a target—PhGdh—that is involved in breast cancer. Now the team is screening the complete set of human metabolic genes to identify additional cancer targets.

TOOLS5 Metabolically, man or mouse? Massachusetts researchers have created mice bearing

human ectopic artificial livers. The animals are healthy and immunocompetent, which should give more consistent results when testing for drug metabolism, drug-drug interactions and drug-induced liver injury. however, scalability is an issue.

PUBLIC-PRIVATE INTERFACE7 Gap-filling alliance Instead of taking discoveries from universities and

forming companies, BioPontis starts with its knowledge of industry's portfolio needs and works backward. Its alliance so far includes Merck, Pfizer, Janssen Biotech and eight universities.

THE DISTILLERY9 This week in therapeutics Ameliorating autoimmune disease by inducing Th17 cell

migration to the gut; preventing influenza infection with broadly neutralizing antibodies against influenza A virus hA; treating Charcot-Marie-Tooth disease with hdAC6 inhibitors; and more…

15 This week in techniques Zinc-finger nuclease–mediated genome editing to generate

isogenic, pluripotent cell lines; hGf/Sf fragments as MET agonists and antagonists; in vivo fluorescent imaging of β cell mass using a GLP-1R–targeted exendin-4 analog; and more…

INDEXES16 Company and institution index16 Target and compound index

Epizyme connects the DOTsBy Joanne Kotz, Senior Editor

Epizyme Inc. has reported the first in vivo data for one of the histone methyltransferase DOT1L inhibitors identified at the company, showing the compound increased overall survival in a mouse model of mixed-lineage leukemia.1 According to the company, the data provide proof of concept for targeting this class of epigenetic enzymes. After selecting a clinical candidate, Epizyme intends to file an IND and take DOT1L inhibi-tors into the clinic in this leukemia.

Mixed-lineage leukemia (MLL) is an aggressive subset of acute leu-kemias with an annual incidence of about 4,000 patients in the U.S and Europe. Chemotherapy or human stem cell transplant, the standard treat-ments, are often ineffective.

The disease is characterized by chromosomal translocations of the gene encoding the histone methyltransferase myeloid-lymphoid or mixed-lineage leukemia (MLL; HRX). These rearrangements lead to the formation of various MLL fusion proteins, which recruit a second histone methyltransferase, DOT1L. This recruitment of DOT1L trig-gers oncogenic overexpression of multiple leukemogenic genes.

Previous research had shown that DOT1L is essential for the develop-ment of MLL.2

“There is a clear mechanistic rationale for a DOT1L inhibitor in MLL,” said Robert Copeland, EVP and CSO of Epizyme.

“A number of genetic studies have pointed to an essential role for the histone methyltransferase DOT1L in the proliferation of acute myeloge-nous leukemias transformed by MLL fusion proteins. DOT1L has therefore been seen as an excellent target for the specific targeting of this subgroup of AMLs,” added Kristian Helin, CSO of EpiTherapeutics ApS.

EpiTherapeutics is developing small molecule inhibitors of histone methyltransferases and histone demethylases.

Using the crystal structure of DOT1L and the chemical structure of the enzyme’s substrate as guides, Epizyme designed EPZ004777. In vitro, the small molecule inhibited DOT1L with an IC50 of 400 pM and showed at least 1,000-fold selectivity for DOT1L over 9 other histone methyltrans-ferases. In MLL cell lines, EPZ004777 decreased expression of leukemo-genic genes targeted by the MLL oncogenic fusion protein and inhibited proliferation compared with vehicle controls.

Epizyme, along with academic collaborators at the Dana-Farber Cancer Institute, Children’s Hospital Boston and Harvard Medical School,

“There is a clear mechanistic rationale for a DOT1L inhibitor in MLL.”

—Robert Copeland, Epizyme Inc.

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 2

analysis COVER STORy

EDITORIALEditor-in-Chief: karen Bernstein, Ph.d.Managing Editor: Gaspar Taroncher-Oldenburg, Ph.d.Executive Editor: Steve EdelsonSenior Editors: Tracey Baas, Ph.d.; Joanne kotz, Ph.d.Writers: Aaron Bouchie; Chris Cain, Ph.d.; Michael flanagan; Tim fulmer, Ph.d.; Michael J. haas; Stephen hansen; kai-Jye Lou; Lauren Martz; Lev Osherovich, Ph.d.; Steve UsdinResearch Director: Walter yangResearch Manager: kevin LehnbeuterProduction Editors: Brandy Cafarella; Sabina Eberle; Carol EvangelistaCopy Editor: Nicole deGennaroEditorial Assistant: Mark ZipkinDesign: Claudia Bentley; Miles daviesFor inquiries, contact editorial@scibx.com

PUBLISHINGPublisher: Peter Collins, Ph.d.Associate Publishers: Gaspar Taroncher-Oldenburg, Ph.d.; Eric PierceMarketing: Sara Girard; Rosy RogersTechnology: Anthony Barrera; Julia kulikovaSales: Ron Rabinowitz; dean Sanderson; Tim Tulloch

OFFICES BioCentury Publications, Inc.San franciscoPO Box 1246San Carlos, CA 94070-1246T: +1 650 595 5333

Chadds ford223 Wilmington-West Chester PikeChadds ford, PA 19317T: +1 610 558 1873

Chicago20 N. Wacker drive, Suite 1465Chicago, IL 60606-2902T: +1 312 755 0798

Oxford287 Banbury RoadOxford OX4 7JAUnited kingdomT: +44 (0)18 6551 2184

Washington, dC2008 Q Street, NW, Suite 100Washington, dC 20009T: +1 202 462 9582

Nature Publishing GroupNew york75 Varick Street, 9th floorNew york, Ny 10013-1917T: +1 212 726 9200

LondonThe Macmillan Building4 Crinan StreetLondon N1 9XW United kingdomT: +44 (0)20 7833 4000

TokyoChiyoda Building 6f2-37 IchigayatamachiShinjuku-ku, Tokyo 162-0843 JapanT: +81 3 3267 8751

SciBX is produced by BioCentury Publications, Inc. and Nature Publishing GroupJoint 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 © 2011 Nature Publishing Group ALL RIGhTS RESERVEd. No part of the SciBX publication or website may be copied, reproduced, retransmitted, disseminated, sold, distributed, published, broadcast, circulated, commercially exploited or used to create derivative works without the written consent of the Publishers. Information provided by the SciBX publication and website is gathered from sources that the Publishers believe are reliable; however, the Publishers do not guarantee the accuracy, completeness, or timeliness of the information, nor do the Publishers make any warranties of any kind regarding the information. The contents of the SciBX publication and website are not intended as investment, business, tax or legal advice, and the Publishers are not responsible for any investment, business, tax or legal opinions cited therein.

next tested the inhibitor in animals. In a mouse xenograft model of MLL, continuous infusion of EPZ004777 increased overall survival compared with vehicle infusion.

Data were published in Cancer Cell.“It’s the first evidence for in vivo efficacy for any histone methyl-

transferase inhibitor,” said Copeland. “While the data have important implications for DOT1L in MLL, we also think the data have far-reaching implications for the entire class. We think these data portend success for the entire strategy of targeting histone methyltransferases.”

Moving toward the clinicAccording to Copeland, Epizyme has identified compounds that are “significant improvements” over EPZ004777. “We have a number of inhibitors of DOT1L that are likely good enough to go into the clinic, and we are in the late stages of final characterization,” he said.

The company has not provided a timeline for an IND filing. How-ever, Copeland did say that the company is “progressing aggressively to the clinic.”

One question is whether a clinical candidate can block the target for a sufficient duration with an acceptable therapeutic window.

Patrick Trojer, director of biology at Constellation Pharmaceuticals Inc., said extended inhibition by histone methyltransferase inhibitors might be necessary to achieve a therapeutic benefit. He noted that data in the paper show a lag time of days before the DOT1L inhibitor has an effect on target gene expression and cell proliferation.

He added that these results are consistent with Constellation’s expe-rience with inhibiting certain histone methyltransferases. Constella-tion is targeting histone methyltransferases, histone demethylases and bromodomain-containing proteins.

SciBX: Science–Business eXchange

SciBX welcomes editorial queries, comments and press releases.

To contact the editorial team at SciBX please e-mail editorial@scibx.com

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 3

analysis COVER STORy

The results in the paper suggest toxicity might be an issue, said Helin, who also is director of the Biotech Research & Innovation Centre at the University of Copenhagen. The mouse data show inhibiting DOT1L is “not overly toxic,” but the DOT1L inhibitor did lead to increases in the number of white blood cells in a short-term assay. “Therefore, unfortunately long-term treatment might lead to more severe side effects,” he added.

Copeland countered that “the hematologic effects are rather minor, and with the improved compounds we are pursuing for clinical applica-tions we remain confident in our ability to achieve an attractive thera-peutic index.”

Outside MLLEpizyme also is exploring the potential of DOT1L inhibitors outside of MLL. “We are empirically evaluating the inhibitor in other cancer types,” said Copeland.

“There’s not a clear genetic link that we know of yet to cancers other than MLL,” said Scott Armstrong, a coauthor on the paper and a coleader of the leukemia program at Dana-Farber.

He did say the hox genes, which are regulated by the MLL protein, are highly expressed in 30%–40% of acute myelogenous leukemias (AMLs) and

in many other cancers. Although it has not yet been demonstrated, DOT1L might be playing a role, suggested Armstrong, who also is an associate pro-fessor in the Department of Pediatrics at Harvard Medical School and in hematology/oncology at Children’s Hospital Boston.

Epizyme has filed patent applications covering composition of matter on its DOT1L inhibitors. Kotz, J. SciBX 4(30); doi:10.1038/scibx.2011.841 Published online Aug. 4, 2011

REfERENCES1. daigle, S.R. et al. Cancer Cell; published online July 12, 2011;

doi:10.1016/j.ccr.2011.06.009 Contact: Roy M. Pollock, Epizyme Inc., Cambridge, Mass. e-mail: rpollock@epizyme.com

2. Nguyen, A.T. & Zhang, y. Genes Dev. 25, 1345–1358 (2011)

COMPANIES ANd INSTITUTIONS MENTIONEd Children’s Hospital Boston, Boston, Mass. Constellation Pharmaceuticals Inc., Cambridge, Mass. Dana-Farber Cancer Institute, Boston, Mass. EpiTherapeutics ApS, Copenhagen, denmark Epizyme Inc., Cambridge, Mass. Harvard Medical School, Boston, Mass. University of Copenhagen, Copenhagen, denmark

The Scientific Acumen of Nature Publishing Groupplus

The Business Intelligence of BioCentury Publications, Inc.in a single publication

Can you afford not to subscribe?Visit scibx.com for details on how to subscribe to SciBX

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 4

analysis TARGETS & MEChANISMS

Agios’ high metabolismBy Steven Edelson, Executive Editor

Massachusetts Institute of Technology, Agios Pharmaceuticals Inc. and other collaborators have used an RNAi-based in vivo screening technol-ogy to discover cancer targets directly related to tumor metabolism. The team applied the approach to a subset of metabolic genes and identified phosphoglycerate dehydrogenase, a key enzyme in serine biosynthesis, as being involved in breast cancer.1

The same team is now screening the complete set of human metabolic genes to identify additional cancer targets.

“The whole premise of starting Agios was looking for new oncology targets and coming at cancer from a different angle than signal transduction and signaling networks—instead looking at metabolic enzymes rewired by cancers to feed their needs and growth potential,” said CEO David Schen-kein. “We said from the start that a core competency we needed to build was the ability to do flux biochemistry studies to see how metabolites are moving. This paper is a glimpse at one of the toolsets we’ve created.”

Flux is the rate of metabolite turnover in a cell. Cancer cells require high metabolic fluxes of carbon metabolism–derived metabolites that are used as cellular building blocks to sustain tumor growth.

Whereas previous research had shown that estrogen receptor–negative breast cancer patients had higher levels of phosphoglycerate dehydrogenase (PHGDH) mRNA than estrogen receptor–negative patients,2 the current study provides the first proof that this enzyme is metabolically linked to tumor proliferation.

PHGDH catalyzes the first step in the serine biosynthesis pathway. Some cancer cells hijack that pathway and use it to ramp up production of proteins and nucleotides required for proliferation.

The team, led by David Sabatini, a member of the Whitehead Institute for Biomedical Research and an associate professor of biology at MIT, started with a list of 2,752 genes that encode all known human metabolic enzymes and small molecule transporters. From there, the researchers used publicly available oncogenomic information to whittle down the list to 133 genes most likely to yield cancer targets.

For example, the list included genes differentially expressed in tumor versus normal tissues or genes already known to be highly expressed in aggressive breast cancer.

Next, the group used an RNAi-based approach to screen the genes in mice. The list of resulting hits was then prioritized based on known cancer-related genomic amplification data, resulting in the identification of PHGDH as essential for tumorigenesis.

The team also used flux analysis to determine how the metabolic fluxes around the serine pathway were different in cells with high PHGDH expres-sion compared with in cells that had normal expression. In breast cancer cell lines with high levels of PHGDH, inhibiting the target decreased cell proliferation.

Results were published in Nature.Sabatini is on Agios’ scientific advisory board (SAB). The team also

included researchers from Harvard University.Separately, a Harvard Medical School–MIT team came to similar

conclusions about PHGDH’s role in oncogenesis. That group used an NMR-based spectroscopy approach to study metabolic fluxes involved in diverting glucose-derived metabolites toward cancer cell proliferation. Those findings were published in Nature Genetics.3

This second team was led by Matthew Vander Heiden, assistant profes-sor of biology at MIT, and Lewis Cantley, professor of systems biology at Harvard Medical School. Both are members of Agios’ SAB.

“All cancer cells need to solve a problem: the conversion of glutamate to α-ketoglutarate,” an intermediate in the citric acid cycle that is used by cancer cells to create backbones necessary to synthesize both nucleotides and nucleic acids, said lead author Richard Possemato, a postdoctoral fellow at the Whitehead Institute. “In the ER-negative breast cancer cells we used, the serine biosynthesis pathway provides a significant amount of that flux.”

The citric acid cycle helps convert carbohydrates, fats and proteins into carbon dioxide and water to generate energy for the cell.

Agios CSO Scott Biller said the in vivo aspect of the screening technol-ogy “is very important—we’ve all been misled by things that happen in a dish. Knocking out genes in a multiplexed format in an actual tumor is a powerful technology.”

All encompassingBoth Agios and the Whitehead Institute now want to expand the screening technology to the entire set of genes for human metabolic enzymes and transporters.

“The paper picked out the high-priority genes, but we want to have a broader systems approach,” said Possemato. “We want to tease out any pathways and start to get a big-picture view of the essentiality of cancer metabolism.”

Added Biller, “The published work is basically a pilot screen—now we’re screening the entire metabolome.”

The screening is being done in collaboration with Sabatini.As for PHGDH itself, Agios hasn’t disclosed what its plans are. The

company’s lead program, which is in preclinical development, focuses on a cancer metabolism target called isocitrate dehydrogenase 1 (IDH1). Agios also has a discovery-stage program focused on a different cancer metabo-lism target—pyruvate kinase M2 isozyme (PKM2).

Edelson, S. SciBX 4(30); doi:10.1038/scibx.2011.842 Published online Aug. 4, 2011

REfERENCES1. Possemato, R. et al. Nature; published online July 14, 2011;

doi:10.1038/nature10350 Contact: david M. Sabatini, Whitehead Institute for Biomedical Research, Cambridge, Mass. e-mail: sabatini@wi.mit.edu

2. Pollari, S. et al. Breast Cancer Res. Treat. 125, 421–430 (2011) 3. Locasale, J.W. et al. Nat. Genet.; published online July 31, 2011;

doi:10.1038/ng.890 Contact: Matthew G. Vander heiden, Massachusetts Institute of Technology, Cambridge, Mass. e-mail: mvh@mit.edu Contact: Lewis C. Cantley, harvard Medical School, Boston, Mass. e-mail: lcantley@hms.harvard.edu

COMPANIES ANd INSTITUTIONS MENTIONEd Agios Pharmaceuticals Inc., Cambridge, Mass. Harvard Medical School, Boston, Mass. Harvard University, Cambridge, Mass. Massachusetts Institute of Technology, Cambridge, Mass. Whitehead Institute for Biomedical Research, Cambridge, Mass.

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 5

analysis TOOLS

Metabolically, man or mouse?By Tracey Baas, Senior Editor

Massachusetts researchers have created mice with human ectopic artificial livers that were used to evaluate human drug metabolism, drug-drug inter-actions and drug-induced liver injury in a proof-of-principle study.1 Unlike animal models that are currently under development for monitoring liver toxicity, the new mice are healthy and immuno-competent, which might give a better picture of outcomes in humans.

The artificial livers consist of a porous polyethylene glycol (PEG) scaffold encapsulating three cell types: human hepatocytes to carry out the liver’s metabolic functions and mouse fibro-blasts and human liver endothelial cells to provide biological and chemical signals necessary for hepatocyte function (see Figure 1, “Human ectopic artificial liver mouse”).

In addition to providing support, the scaffold helps prevent the mouse immune system from attacking the transplanted cells, allowing the livers to be implanted for up to eight days in immunocompetent mice or indefinitely in immunocompromised animals.

Gene expression assays confirmed that the livers expressed cytochrome P450 3A4 (CYP3A4), CYP1A2, CYP2D6, CYP2E1 and CYP2C, which together metabolize more than 90% of known drugs.

In mice with artificial liver implants that received the anticoagulant coumarin or the antihypertensive debrisoquine, metabolites of those drugs that are observed in humans but not in mice turned up in serum and urine. That finding indicated the activity of human liver CYP2A6 and CYP2D6 enzymes and suggested the mice could be used to study human drug metabolism.

The researchers also used the engineered mice to recapitulate the effects of a known drug-drug interaction between the antibiotic rifampin, a cytochrome P450 inducer, and the analgesic acetaminophen. Animals receiving the combination had greater hepatocellular injury, indicative of higher levels of the hepatotoxic metabolite N-acetyl-p-benzoquinone, than mice given either compound alone.

The findings were published in the Proceed-ings of the National Academy of Sciences.

The team was led by Sangeeta Bhatia, profes-sor of health sciences and technology, and elec-trical engineering and computer science at the Massachusetts Institute of Technology and chair of Hepregen Corp.’s scientific advisory board. The paper also included researchers from MIT, Harvard University, the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

“The previous approach of injecting human hepatocytes into immu-nodeficient mice with liver injury to repopulate the liver provides a liver with a mixed metabolism” of both human and mouse, said Alice Chen, first author on the paper and a graduate student in Bhatia’s laboratory. “This method of humanization is highly unpredictable and variable and produces mice that are not very healthy. Human ectopic artificial livers can be implanted into normal, healthy mice and provide consistent results.”

Model citizensNext steps include using the mice to validate known metabolic character-istics and drug-drug interactions in larger panels of marketed drugs, as well as adapting the model for drug development of human liver diseases, including HCV and malaria infection.

Nico Scheer, head of ADMET R&D at Taconic Farms Inc., thinks “the human ectopic artificial liver mice might indeed be useful for studying human metabolism and drug-drug interactions in late-stage drug develop-ment ADMET studies.”

Primary human hepatocytes

Human liver endothelial cells

Mouse �broblasts

Polymer PEG-DA scaffold + optimal porosity + adhesion peptides

Human ectopicarti�cial liver (HEAL) Humanized

mouseHuman metabolites

Drug toxicity

Drug-druginteractions

Drug exposure viadifferent routes

Figure 1. Human ectopic artificial liver mouse. Primary human hepatocytes are cocultivated with stabilizing stromal mouse fibroblasts on collagen-coated plates for 7–10 days. They are then encapsulated with human liver endothelial cells in polyethylene glycol–diacrylate (PEG-DA) scaffolds derivatized with adhesion Arg-Gly-Asp-Ser (RGdS) peptides. The human ectopic artificial livers (hEALs) are about 20 mm in diameter and 250 µm thick, with about 0.5×106 human hepatocytes. They are surgically placed intraperitoneally into laboratory mice, in which the implants become engrafted and vascularized. The hEAL mice provide models to study human metabolites, drug expo-sure via different routes, drug-drug interactions and drug toxicity. (figure based on figure 1 in ref. 1.)

“The human ectopic artificial liver mice might indeed be useful for studying human metabolism and drug-drug interactions in late-stage drug development ADMET studies.”—Nico Scheer, Taconic Farms Inc.

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 6

analysis TOOLS

He did say the approach also has certain limitations. For exam-ple, the presence of mouse hepatocytes might confound metabolic interpretation.

Scheer and collaborators recently produced a mouse model using a targeted insertion strategy to humanize four genes involved in drug metabolism: pregnane X receptor (PXR), constitutive androstane receptor (NR1I3; CAR), CYP3A4 and CYP3A7. The group used the model to predict human drug-drug interactions2 and now is working toward more complex mouse lines with additional humanization. The group believes the model may avoid the use of nonhuman primates for some drug-drug interaction studies.

Salman Khetani, director of research at Hepregen, said the mice with humanized ectopic artificial livers will have to be more thoroughly evalu-ated to see if they are better able to predict clinical outcomes than existing model systems.

The key question, he said, is whether the mice “can be used in a scalable business model while reducing clinical trial attrition rates and liabilities. They will be better positioned to answer that question after using their mice to characterize larger panels of marketed drugs to validate known metabolic characteristics.”

Hepregen is playing further upstream in the drug development process than mouse models of drug-drug interactions. The company has com-mercialized a microliver chip platform, HepatoPac, through a service offer-ing high throughput screening of large panels of drugs in stable human hepatocytes.

“We have used HepatoPac to predict 75%–80% of known clinical toxici-ties in a panel of 200 different drug candidates and have identified up to 82%

of clinical drug metabolites in a panel of 32 compounds with Pfizer Inc.3,4 The platform is capable of evaluating human drug metabolism, drug-drug interactions and drug-induced hepatic injury,” said Khetani. “In vitro and in vivo models address different parts of the drug development pipeline—they speak to a different audience.”

MIT has filed for a patent covering the mice. The model is available for licensing.

Baas, T. SciBX 4(30); doi:10.1038/scibx.2011.843 Published online Aug. 4, 2011

REfERENCES1. Chen, A.A. et al. Proc. Natl. Acad. Sci. USA; published online

July 11, 2011; doi:10.1073/pnas.1101791108 Contact: Sangeeta Bhatia, Massachusetts Institute of Technology, Cambridge, Mass. e-mail: sbhatia@mit.edu Contact: Alice Chen, same affiliation as above e-mail: aachen@mit.edu

2. hasegawa, M. et al. Mol. Pharmacol.; published online May 31, 2011; doi:10.1124/mol.111.071845

3. khetani, S.R. & Bhatia, S.N. Nat. Biotechnol. 26, 120–126 (2008)4. Wang, W.W. et al. Drug Metab. Dispos. 38, 1900–1905 (2010)

COMPANIES ANd INSTITUTIONS MENTIONEd Brigham and Women’s Hospital, Boston, Mass. Broad Institute of MIT and Harvard, Cambridge, Mass. Dana-Farber Cancer Institute, Boston, Mass. Harvard University, Cambridge, Mass. Hepregen Corp., Medford, Mass. Massachusetts Institute of Technology, Cambridge, Mass. Pfizer Inc. (NySE:PfE), New york, N.y. Taconic Farms Inc., hudson, N.y.

Can You Afford Not to Read SciBX?

According to MEDLINE®, the U.S. National Library of Medicine’s® premier bibliographic database of articles in life sciences, over 775,000 articles were added to the database in 2009 alone —an average of

almost 15,000 new articles every week.

Can you afford to miss investment opportunities?

Can you afford to miss emerging competition?

SciBX is the single source for scientific context, commercial impact and the critical next steps.

Visit scibx.com for details on how to subscribe to SciBX

SciBX: Science–Business eXchange

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 7

analysis PUBLIC-PRIVATE INTERfACE

Gap-filling allianceBy Kai-Jye Lou, Staff Writer

BioPontis Alliance LLC is taking a fresh approach to addressing the translational gap—instead of taking discoveries from universities and forming companies, BioPontis starts with its knowledge of industry’s portfolio needs and works backward. The company hopes to close a $50 million pilot fund by year end and start its first two R&D projects early next year.

The model is one of a number of experiments that early stage inves-tors are running to solve the translational gap. These include VCs such as Atlas Venture and Index Ventures that are setting up single-project companies with minimal infrastructure,1,2 as well as firms like PureTech Ventures that start with an unmet need, look for potential solutions in academia, then establish companies to drive these solutions to clinical and commercial milestones.

For BioPontis founder and CEO Richard Basile, the translational gap is characterized by a dearth of risk capital, a lack of scientific develop-ment expertise to develop technologies to meet industry’s standards and the absence of a system that provides access to university IP while keeping the university as a partner through the technology development process.

“The legacy models in this space, such as accel-erators and incubators, have not been particularly successful at solving the valley of death problem,” Basile told SciBX. “VCs have withdrawn from this space as well, though recently some have been coming back in the form of small funds for discovery research. However, these funds still lack the scientific expertise and existing industry agree-ments that we bring to this space.”

Part of the problem, he said, is that conventional incubators are focused on forming companies around individual discoveries.

“At this early stage, we think establishing a new company is a very inefficient means to go about developing a technology,” he told SciBX. “Our model avoids many of the costs associated with establishing a new company such as hiring management and building infrastructure.”

“At BioPontis, nobody’s career or investment dollars will be tied to any one particular technology or idea—as would be the case with the found-ing of new companies or inside the R&D divisions of biopharmaceutical companies where programs compete for funding and favor,” he continued. “There is no incentive for us to keep pursuing a technology if its position is steadily weakening. This means we can test each of our projects and let the science establish itself.”

Relationships at both endsBioPontis was founded in 2009 as a combination of an investment fund and an R&D company.

BioPontis’ areas of focus are cancer, neurology, inflammation and infectious diseases. Thus far, the company has announced translational research agreements with three pharmas: Merck & Co. Inc., Pfizer Inc. and most recently the Janssen Biotech Inc. unit of Johnson & Johnson. BioPontis also has a network of eight university partners and plans to announce additional university partnerships this year.

BioPontis’ industry partners provide the firm with confidential guid-ance on priorities for their product portfolios, advice on product devel-opment objectives and experimental design, and access to technology development, market research and clinical resources.

Pharmas may even provide BioPontis with knowledge of negative data from the pharma’s internal efforts against a target, noted Barbara Handelin, president and principal at BioPontis.

“These data give us details on what failed to work and why,” she said. “Historically, details behind failures are rarely published and shared, but the industry is collectively realizing that it is losing a lot of value in repeat-ing the same mistakes. These companies will also share in knowledge of the negative data from projects in the BioPontis portfolio that fail to meet criteria for advancement.”

BioPontis uses its knowledge of industry’s portfolio needs to guide the selection of technologies from its partners in academia, which BioPontis dubs University Alliance Partners.

The current University Alliance Partners are Columbia University, the Memorial Sloan-Kettering Cancer Center, New York University, the University of Florida, the University of Pennsylvania, the University of Virginia and The University of North Carolina at Chapel Hill. One University Alliance Partner has not yet been disclosed.

Under the deals with its University Alliance Partners, BioPontis gets nonexclusive access to the partners’ IP portfolio. Technologies that make

it past an initial triage stage are moved through a more formal due dili-gence step in which BioPontis receives a temporary, exclusive option on the technology.

BioPontis reviews the technology and determines whether or not it will license the IP. If BioPontis declines, the IP becomes available for licensing to other parties.

“Our model incentivizes us to identify failures, to focus resources on projects that appear to be more promising and to shift resources away from those that are starting to show signs of weakness,” said Basile.

Red flags, he said, could come in the form of poor IP position or tech-nical gaps.

For example, “A technology covering a biologic for cancer showed some very interesting effects and had a solid IP position, but we did not think we would be able to tease out a pragmatic synthesis approach that would meet regulatory and manufacturing requirements,” Basile told SciBX. “The technical gaps made this particular technology unsuitable for further consideration.”

If a technology passes the diligence phase, BioPontis takes an exclusive worldwide license to the technology for all uses. The university receives no up-front payment, receiving instead a prorated share of the total value generated in any deal BioPontis does for the technology.

According to Basile, this deal structure incentivizes both BioPontis and its university partner to work together to maximize the exit value of technology assets.

Once BioPontis licenses a technology, its job is to establish a devel-opment plan, carry out validation studies and enhance the existing IP position by moving suitable candidates and leads through IND-enabling studies.

“Our model avoids many of the costs associated with establishing a new company such as hiring management and building infrastructure.”

—Richard Basile, BioPontis Alliance LLC

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 8

analysis PUBLIC-PRIVATE INTERfACE

“We have lead development scientists to take care of our technology assets,” said Basile. “They are responsible for overseeing the development pathway and the experiments that are to be carried out. Our board will review the development and progress of each asset and take a Darwinian view on which assets to continue developing.”

The development scientists use the resources in BioPontis’ R&D network, which include CROs like Taconic Farms Inc., to carry out validation studies.

“We anticipate exiting assets from BioPontis that have at minimum reached an optimized small molecule, protein or antibody that would be ready for clinical testing,” said Basile. “The most mature exit would be after a first-in-human study, which could be a Phase 0 trial or a proof-of-biology study.”

Basile expects the majority of exits for BioPontis’ technology assets will be licensing deals in which an industry partner receives rights to the asset in exchange for an up-front payment, milestones and royalties. He said another potential exit scenario could involve the industry partner paying BioPontis to continue incubating the asset.

Company milestonesBioPontis hopes to close its $50 million pilot fund by year end. The com-pany’s goal is to mine through 1,000–2,000 technology assets by year 3 of the fund, vet and invest in 15–25 assets by year 5 and exit 5 assets at the optimized lead or the IND-ready stage in years 4–10.

BioPontis hopes to raise a second, larger fund as it is able to establish the scalability and reproducibility of its model.

The firm is conducting diligence on 6 assets and plans to move 2 of these

technologies into development within 90 days of closing the pilot fund.One of the assets in the final stages of diligence covers the target

hormonally up-regulated Neu-associated kinase (HUNK; B19). In Febru-ary, researchers at the Perelman School of Medicine at the University of Pennsylvania published a study suggesting that a HUNK inhibitor might increase breast cancer susceptibility to existing anti-HER2 (EGFR2; ERBB2; neu) therapeutics.3,4

Lou, K.-J. SciBX 4(30); doi:10.1038/scibx.2011.844 Published online Aug. 4, 2011

REfERENCES1. flores, d. & Bernstein, k. BioCentury 17(40), A1–A10; Sept. 14, 20092. Lawrence, S. BioCentury 19(10), A13–A14; feb. 28, 20113. yeh, E.S. et al. J. Clin. Invest. 121, 866–879 (2011) 4. Martz, L. SciBX 4(10); doi:10.1038/scibx.2011.271

COMPANIES ANd INSTITUTIONS MENTIONEd Atlas Venture, Cambridge, Mass. BioPontis Alliance LLC, Raleigh, N.C. Columbia University, New york, N.y. Index Ventures, London, U.k. Johnson & Johnson (NySE:JNJ), New Brunswick, N.J. Memorial Sloan-Kettering Cancer Center, New york, N.y. Merck & Co. Inc. (NySE:MRk), Whitehouse Station, N.J. New York University, New york, N.y. Perelman School of Medicine at the University of Pennsylvania,

Philadelphia, Pa. Pfizer Inc. (NySE:PfE), New york, N.y. PureTech Ventures, Boston, Mass. Taconic Farms Inc., hudson, N.y. University of Florida, Gainesville, fla. The University of North Carolina at Chapel Hill, Chapel hill, N.C. University of Pennsylvania, Philadelphia, Pa. University of Virginia, Charlottesville, Va.

SciBXSciBX: Science–Business eXchange—transform your ability to efficiently identify and

evaluate new developments in science and technology that have commercial and investment potential within the biotechnology and pharmaceutical arena.

Subscribe today at scibx.com

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 9

ThE dISTILLERy

This week in therapeuticsTHE 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.

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Autoimmune diseaseAutoimmune; multiple sclerosis (MS)

CD3; CC chemokine receptor 6 (CCR6; CD196); chemokine CC motif ligand 20 (CCL20; MIP3A)

Mouse studies suggest promoting T helper type 17 (Th17) cell migration into the gut could help treat MS and other autoimmune diseases. In mice, a CD3-specific antibody or a Staphylococcus aureus antigen induced CCR6- and CCL20-dependent accumulation of Th17 cells in the small intestines and promoted the generation of a newly identified class of immunosuppressive regulatory Th17 cells compared with antibody or antigen controls. In an MS mouse model, CD3 antibody–induced accumulation of Th17 cells in the small intestines or transfer of regulatory Th17 cells suppressed disease pathology, whereas saline did not. Next steps include identifying the mechanisms in the small intestines that convert proinflammatory Th17 cells into regulatory Th17 cells.

SciBX 4(30); doi:10.1038/scibx.2011.845 Published online Aug. 4, 2011

Unpatented; licensing status not applicable

Esplugues, E. et al. Nature; published online July 17, 2011; doi:10.1038/nature10228 Contact: Richard A. Flavell, Yale School of Medicine, New Haven, Conn. e-mail: richard.flavell@yale.edu Contact: Enric Esplugues, same affiliation as above e-mail: enric.esplugues@yale.edu

Rheumatoid arthritis (RA)

Unknown Rat studies identified peptides that could help treat RA. In arthritic rats, in vivo phage screening identified a trio of nine-amino-acid peptides that accumulated in inflamed joints. In a rat model of RA, i.v. infusion with two of the three peptides decreased disease pathology compared with saline infusion. Next steps could include optimizing the peptides and evaluating them as carrier molecules for other therapeutics.

SciBX 4(30); doi:10.1038/scibx.2011.846 Published online Aug. 4, 2011

Patent and licensing status unavailable

Yang, Y.-H. et al. Proc. Natl. Acad. Sci. USA; published online July 18, 2011; doi:10.1073/pnas.1103569108 Contact: Kamal D. Moudgil, University of Maryland School of Medicine, Baltimore, Md. e-mail: kmoud001@umaryland.edu

CancerAcute myelogenous leukemia (AML)

E1A binding protein p300 (EP300; p300); AML1-ETO oncogenic fusion protein

Cell culture and mouse studies suggest inhibiting p300 could help treat AML1-ETO-positive AML. AML1-ETO fusion is the cause of 10%–15% of AML cases. In AML1-ETO fusion–positive cells isolated from patients, a p300 inhibitor lowered growth compared with control compound. In mice, injection of leukemia cells pretreated with a p300 inhibitor led to greater survival than injection of leukemia cells receiving control compound. Next steps include inhibiting p300 in additional mouse models of leukemia.

SciBX 4(30); doi:10.1038/scibx.2011.847 Published online Aug. 4, 2011

Patent application filed; available for licensing

Wang, L. et al. Science; published online July 14, 2011; doi:10.1126/science.1201662 Contact: Stephen D. Nimer, Memorial Sloan-Kettering Cancer Center, New York, N.Y. e-mail: nimers@mskcc.org

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 10

ThE dISTILLERy

This week in therapeutics (continued)

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Breast cancer Phosphoglycerate dehydrogenase (PHGDH)

In vitro and mouse studies suggest inhibiting PHGDH or other components of the serine biosynthetic pathway could help treat breast cancers. In breast cancer cells with PHGDH overexpression, PHGDH-targeting small hairpin RNA decreased cellular serine biosynthetic pathway flux and proliferation compared with control shRNA. Mice with PHGDH shRNA–expressing human breast cancer cells had less tumor growth than mice with control shRNA–expressing human breast cancer cells. Next steps include screening the entire set of human metabolic enzymes and transporters to test their involvement in cancer cell metabolism (see Agios' high metabolism, page 4).

SciBX 4(29); doi:10.1038/scibx.2011.848 Published online July 28, 2011

Patent and licensing status undisclosed

Possemato, R. et al. Nature; published online July 14, 2011; doi:10.1038/nature10350 Contact: David M. Sabatini, Whitehead Institute for Biomedical Research, Cambridge, Mass. e-mail: sabatini@wi.mit.edu

Cancer Cyclin dependent kinase 5 (CDK5)

In vitro studies suggest inhibiting CDK5 could help prevent metastatic cancers. In cellular models of metastasis and in human cancer cell lines, two CDK5 inhibitors, including purvalanol, prevented formation of invadopodia, which are cell membrane protrusions that enable cancer cell invasion and metastasis, compared with vehicle. In a human ovarian cancer cell line resistant to paclitaxel, purvalanol blocked invadopodia formation compared with vehicle. Ongoing work includes testing the effects of CDK5 inhibitors and paclitaxel on metastasis in animal models of cancer. AT7519, an inhibitor of CDK1, CDK2, CDK4, CDK5 and CDK9 from SuperGen Inc., is in Phase II testing to treat multiple myeloma (MM) and Phase I testing to treat mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and solid tumors. BAY 1000394, a pan-CDK inhibitor from Bayer AG, is in Phase I testing to treat cancer.

SciBX 4(30); doi:10.1038/scibx.2011.849 Published online Aug. 4, 2011

Unpatented; available for licensing or partnering

Quintavelle, M. et al. Sci. Signal.; published online July 26, 2011; doi:10.1126/scisignal.2002032 Contact: Sara A. Courtneidge, Sanford-Burnham Medical Research Institute, La Jolla, Calif. e-mail: courtneidge@sanfordburnham.org

Cancer HER2 (EGFR2; ERBB2; neu); signal transducer and activator of transcription 3 (STAT3)

Mouse studies suggest delivering STAT3 inhibitor–loaded nanoparticles to the tumor microenvironment could boost the efficacy of HER2 cancer vaccines. In a mouse model of Her2-positive mammary cancer, a HER2 vaccine plus a tumor-targeted nanoparticle loaded with a STAT3 inhibitor protected against tumor recurrence, whereas either treatment alone did not. Next steps include evaluating nanoparticle-mediated delivery of multiple therapeutics and testing the loaded nanoparticles in mice with human tumors.

SciBX 4(30); doi:10.1038/scibx.2011.850 Published online Aug. 4, 2011

Unpatented; unavailable for licensing

Liao, D. et al. Cancer Res.; published online July 22, 2011; doi:10.1158/0008-5472.CAN-11-1264 Contact: Ralph A. Reisfeld, The Scripps Research Institute, La Jolla, Calif. e-mail: reisfeld@scripps.edu

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 11

ThE dISTILLERy

This week in therapeutics (continued)

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Cancer LINE1 retrotransposable element 1 (L1RE1)

In vitro and mouse studies suggest reverse transcriptase inhibitors could help treat cancer. In a human melanoma cell line, a lead pyrimidinone analog of an L1RE1-encoded reverse transcriptase inhibitor blocked 95% of growth at 25 µM. In mice with melanoma xenografts, the lead compound decreased tumor growth compared with efavirenz or vehicle. Ongoing work includes testing the compound in animal models of colon, lung and prostate cancer. Merck & Co. Inc. and Bristol-Myers Squibb Co. market the non-nucleoside reverse transcriptase inhibitor Sustiva efavirenz to treat HIV/AIDS.

SciBX 4(30); doi:10.1038/scibx.2011.851 Published online Aug. 4, 2011

Unpatented; available for licensing or partnering

Sbardella, G. et al. J. Med. Chem.; published online July 14, 2011; doi:10.1021/jm200734j Contact: Gianluca Sbardella, University of Salerno, Fisciano, Italy e-mail: gsbardella@unisa.it Contact: Antonello Mai, Sapienza University of Rome, Rome, Italy e-mail: antonello.mai@uniroma1.it

Cancer Phosphoglycerate dehydrogenase (PHGDH)

Human sample and cell culture studies suggest inhibiting PHGDH could help treat cancer. In a genomic analysis of approximately 3,000 patient samples, PHGDH was identified as frequently amplified, particularly in melanoma. In human cancer cell lines with PHGDH amplification, small hairpin RNA against PHGDH decreased proliferation compared with control shRNA. Next steps could include identifying and evaluating pharmacological PHGDH inhibitors in cancer models (see Agios' high metabolism, page 4).

SciBX 4(30); doi:10.1038/scibx.2011.852 Published online Aug. 4, 2011

Patent and licensing status undisclosed

Locasale, J.W. et al. Nat. Genet.; published online July 31, 2011; doi:10.1038/ng.890 Contact: Matthew G. Vander Heiden, Massachusetts Institute of Technology, Cambridge, Mass. e-mail: mvh@mit.edu Contact: Lewis C. Cantley, Harvard Medical School, Boston, Mass. e-mail: lcantley@hms.harvard.edu

Cancer Thymidylate synthase In vitro studies identified allosteric inhibitors of thymidylate synthase that could help treat cancer. In X-ray diffraction, spectroscopic, kinetic and calorimetric studies, peptides designed to bind the interface between the two monomers of the thymidylate synthase dimer inhibited the enzyme by stabilizing its inactive form. In cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, the most potent peptide inhibitor decreased cell growth comparably to the marketed thymidylate synthase inhibitor 5-fluorouracil. Next steps include mechanistic studies of the peptide at the cellular level. At least seven companies have thymidylate synthase inhibitors in development stages ranging from clinical to marketed to treat cancer.

SciBX 4(30); doi:10.1038/scibx.2011.853 Published online Aug. 4, 2011

Patent applications filed; available for licensing

Cardinale, D. et al. Proc. Natl. Acad. Sci. USA; published online July 27, 2011; doi:10.1073/pnas.1104829108 Contact: M. Paola Costi, University of Modena and Reggio Emilia, Modena, Italy e-mail: mariapaola.costi@unimore.it Contact: Glauco Ponterini, same affiliation as above e-mail: glauco.ponterini@unimore.it Contact: Rebecca C. Wade, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany e-mail: rebecca.wade@h-its.org

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 12

ThE dISTILLERy

This week in therapeutics (continued)

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Infectious diseaseCandida Unknown Cell culture studies identified (S)-2-aminoalkyl

benzimidazoles that could help treat Candida infections. In a panel of 16 Candida clinical isolates, the lead benzimidazole had a mean minimal inhibitory concentration of 2.83 µg/mL compared with 2.18 µg/mL for the antifungal fluconazole. In the same panel, the lead compound had antifungal activity against three fluconazole-resistant strains. EMC microcollections GmbH has the lead benzimidazole in preclinical testing to treat Candida infection. Diflucan fluconazole, a synthetic triazole antifungal from Pfizer Inc., is marketed to treat Candida infection.

SciBX 4(30); doi:10.1038/scibx.2011.854 Published online Aug. 4, 2011

Patented for use as an antimicrobial; licensing status undisclosed

Bauer, J. et al. J. Med. Chem.; published online June 29, 2011; doi:10.1021/jm200571e Contact: Holger Eickhoff, EMC microcollections GmbH, Tuebingen, Germany e-mail: eickhoff@microcollections.de

Influenza virus Influenza A virus hemagglutinin (HA)

In vitro and mouse studies suggest a broadly neutralizing antibody against influenza A virus HA could help treat or prevent influenza infection. In vitro, the mAb F16, isolated from an individual vaccinated against influenza, bound all 16 subtypes of influenza A virus HA and neutralized multiple group 1 and group 2 influenza A viruses. In mouse and ferret models of H1N1, H3N2 or H5N1 viral infection, F16 given before or after viral challenge decreased morbidity and mortality compared with an unrelated control mAb. Humabs BioMed S.A. has F16 in ongoing preclinical testing to prevent or treat influenza infection. Flu-mAb, a universal mAb product that includes broadly neutralizing antibodies against group 1 and group 2 influenza virus from Johnson & Johnson, is in preclinical testing to treat and prevent influenza A viral infections.

SciBX 4(30); doi:10.1038/scibx.2011.855 Published online Aug. 4, 2011

Patented by the Institute for Research in Biomedicine; licensed to Humabs BioMed

Corti, D. et al. Science; published online July 28, 2011; doi:10.1126/science.1205669 Contact: Antonio Lanzavecchia, Institute for Research in Biomedicine, Bellinzona, Switzerland e-mail: lanzavecchia@irb.unisi.ch Contact: John J. Skehel, National Institute for Medical Research, London, U.K. e-mail: skeheljj@nimr.mrc.ac

Malaria Not applicable In vitro and mouse studies identified a series of 1,4-naphthoquinones that could help treat malaria. In vitro, the naphthoquinones had better potency against multidrug-resistant Plasmodium falciparum than chloroquine. The new series of compounds induce a cascade that disrupts the redox balance in red blood cells that is necessary for parasite survival. In mice infected with P. berghei, several of the naphthoquinones decreased parasitemia compared with no treatment. Next steps include obtaining funding for additional mouse studies.

SciBX 4(30); doi:10.1038/scibx.2011.856 Published online Aug. 4, 2011

Patent applications filed; available for licensing

Müller, T. et al. J. Am. Chem. Soc.; published online June 17, 2011; doi:10.1021/ja201729z Contact: Elisabeth Davioud-Charvet, University of Strasbourg, Strasbourg, France e-mail: elisabeth.davioud@unistra.fr

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 13

ThE dISTILLERy

This week in therapeutics (continued)

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Musculoskeletal diseaseSpinal muscular atrophy (SMA)

Survival of motor neuron 1 telomeric (SMN1)

Studies in mice suggest that the peptide hormone prolactin could help treat SMA. In a mouse model of severe SMA, daily intraperitoneal prolactin injections resulted in increased SMN levels, which are decreased in SMA due to mutations in SMN1, better motor function and significantly greater survival (p<0.0001) compared with saline injections. Next steps include optimizing the dosing of prolactin to see if it will result in further improvements in SMN induction and survival.

SciBX 4(30); doi:10.1038/scibx.2011.857 Published online Aug. 4, 2011

Unpatented; licensing status not applicable

Farooq, F. et al. J. Clin. Invest.; published online July 25, 2011; doi:10.1172/JCI46276 Contact: Alex MacKenzie, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada e-mail: mackenzie@cheo.on.ca

NeurologyAddiction Cannabinoid CB2

receptor (CNR2)Mouse studies suggest CNR2 agonists could be useful for treating cocaine abuse and addiction. In mouse models of cocaine addiction, CNR2 agonists inhibited cocaine self-administration and cocaine-enhanced locomotion compared with vehicle. Next steps include studying the effects of CNR2 agonists in rats and primates. Pharmos Corp.’s Cannabinor (PRS-211,375), a CNR2 agonist, is in Phase I testing for inflammation.

SciBX 4(30); doi:10.1038/scibx.2011.858 Published online Aug. 4, 2011

Unpatented; unavailable for licensing

Xi, Z.-X. et al. Nat. Neurosci.; published online July 24, 2011; doi:10.1038/nn.2874 Contact: Zheng-Xiong Xi, National Institute on Drug Abuse, Baltimore, Md. e-mail: zxi@intra.nida.nih.gov

Alzheimer’s disease (AD)

β-Site APP-cleaving enzyme 1 (BACE1)

In vitro and rat studies suggest a class of BACE1 inhibitors could help treat AD. Fragment-based screening, synthesis and in vitro testing of 2-aminoquinoline analogs identified compounds that were low nanomolar inhibitors of BACE1. In a rat model of AD, the lead compound lowered β-amyloid (Aβ) levels in cerebral spinal fluid compared with vehicle. Future studies could include optimizing the lead compound to improve its metabolic stability. At least four companies have BACE1 antagonists in preclinical or Phase I testing for AD.

SciBX 4(30); doi:10.1038/scibx.2011.859 Published online Aug. 4, 2011

Patented by Amgen Inc.; unavailable for licensing

Cheng, Y. et al. J. Med. Chem.; published online June 27, 2011; doi:10.1021/jm200544q Contact: Ted C. Judd, Amgen Inc., Thousand Oaks, Calif. e-mail: tjudd@amgen.com Contact: Yuan Cheng, same affiliation as above e-mail: yuanc@amgen.com

Neuropathy Histone deacetylase 6 (HDAC6); heat shock 27 kDa protein 1 (HSPB1; HSP27); tubulin

Mouse studies suggest HDAC6 inhibitors could help treat Charcot-Marie-Tooth (CMT) disease caused by HSP27 mutations. Transgenic mice expressing mutant Hsp27 in neurons had CMT disease–like sensorimotor defects compared with controls expressing wild-type Hsp27. In the mutant mice, HDAC6 inhibitors increased motor performance compared with vehicle. Future studies could include testing HDAC6 inhibition in animal models of CMT disease caused by other gene mutations. ACY-1215, an oral selective HDAC6 inhibitor from Acetylon Pharmaceuticals Inc., is in preclinical testing to treat multiple myeloma (MM) and other cancers. KAR3166, an HDAC6 inhibitor from Karus Therapeutics Ltd., is in preclinical testing to treat inflammation. The company’s KAR3000 HDAC6 inhibitor is in lead optimization to treat cancer.

SciBX 4(30); doi:10.1038/scibx.2011.860 Published online Aug. 4, 2011

Patent and licensing status unavailable

D’Ydewalle, C. et al. Nat. Med.; published online July 24, 2011; doi:10.1038/nm.2396 Contact: Ludo Van Den Bosch, Catholic University Leuven, Leuven, Belgium e-mail: ludo.vandenbosch@vib-kuleuven.be

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 14

ThE dISTILLERy

This week in therapeutics (continued)

IndicationTarget/marker/ pathway Summary

Licensing status

Publication and contact information

Pain Dynamin 1-like (DNM1L; DRP1)

Mouse studies suggest DRP1 inhibition could help treat neuropathic pain. In mouse models of neuropathic pain, antisense or pharmacological inhibition of the mitochondrial fission protein Drp1 decreased pain compared with that seen using control antisense or vehicle. Next steps could include testing undisclosed small molecules that inhibit mitochondrial fission.

SciBX 4(30); doi:10.1038/scibx.2011.861 Published online Aug. 4, 2011

Unpatented; licensing status not applicable

Ferrari, L.F. et al. J. Neurosci.; published online Aug. 3, 2011; doi:10.1523/JNEUROSCI.2223-11.2011 Contact: Jon D. Levine, University of California, San Francisco, Calif. e-mail: Jon.Levine@ucsf.edu

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 15

ThE dISTILLERy

This week in techniquesTHE 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 Licensing statusPublication and contact information

Disease modelsZinc finger nuclease (ZFN)-mediated genome editing to generate isogenic, pluripotent cell lines

ZFN-mediated genome editing on pluripotent cell lines could help create new pairs of cell lines for modeling human diseases. As proof of concept, ZFNs were used to insert Parkinson’s disease (PD)-causing point mutations into human embryonic and induced pluripotent stem (iPS) cells. ZFNs also were used to repair PD-causing point mutations in patient-derived iPS cells. Next steps could include using ZFN-mediated genome editing to generate isogenic cell line pairs for other diseases. Sangamo BioSciences Inc. has ZFN-based compounds in clinical and preclinical testing for multiple indications.

SciBX 4(30); doi:10.1038/scibx.2011.862 Published online Aug. 4, 2011

Sangamo BioSciences has multiple patents covering the design and use of ZFNs for research and therapeutic applications; licensing status unavailable

Soldner, F. et al. Cell; published online July 14, 2011; doi:10.1016/j.cell.2011.06.019 Contact: Rudolf Jaenisch, Whitehead Institute for Biomedical Research, Cambridge, Mass. e-mail: jaenisch@wi.mit.edu

Drug platformsA recombinant Neisseria meningitidis factor H–binding protein (fHBP)-based vaccine for broad protective immunity

A recombinant fHBP-based vaccine could provide protection against serogroup B N. meningitidis strains. Recombinant fHBPs displaying two recombinant immunodominant regions were tested in a murine bactericidal activity assay and further optimized by fusing two copies of the fHBP to another meningococcal antigen. In mice, the fusion vaccine showed bactericidal activity toward serogroup B N. meningitidis variants 1, 2 and 3. Next steps could include using a mouse challenge model of group B N. meningitidis strains. Novartis AG has the multicomponent meningococcal serogroup B vaccine 4CMenB in Phase III testing.

SciBX 4(30); doi:10.1038/scibx.2011.863 Published online Aug. 4, 2011

Patent and licensing status unavailable

Scarselli, M. et al. Sci. Transl. Med.; published online July 13, 2011; doi:10.1126/scitranslmed.3002234 Contact: Rino Rappuoli, Novartis Vaccines and Diagnostics S.r.l., Siena, Italy e-mail: rino.rappuoli@novartis.com Contact: Lucia Banci, University of Florence, Florence, Italy e-mail: banci@cerm.unifi.it

Hepatocyte growth factor/scatter factor (HGF/SF) fragments as c-met proto-oncogene (MET; HGFR) agonists and antagonists

HGF/SF fragment–based MET agonists and antagonists could be useful for treating wounds or various cancers. Directed evolution and site-directed mutagenesis were used to engineer heat-stable HGF/SF fragments that targeted MET. In cellular assays, the engineered HGF/SF fragments were more stable, had higher expression yields and showed better agonistic or antagonistic activity against MET than wild-type HGF/SF fragments. Next steps include evaluating the HGF/SF fragments in models of wound healing and cancer.

SciBX 4(30); doi:10.1038/scibx.2011.864 Published online Aug. 4, 2011

Patent application filed covering regenerative medicine, cancer and cancer diagnostics; available for licensing from the Stanford University Office of Technology Licensing

Jones, D.S. II et al. Proc. Natl. Acad. Sci. USA; published online July 25, 2011; doi:10.1073/pnas.1102561108 Contact: Jennifer R. Cochran, Stanford University, Stanford, Calif. e-mail: jennifer.cochran@stanford.edu

ImagingIn vivo fluorescent imaging of β cell mass using a glucagon-like peptide-1 receptor (GLP-1R; GLP1R)-targeted exendin-4 analog

In vitro and mouse studies identified an exendin-4 analog–based fluorescent probe that could help assess therapeutic efficacy and disease progression in diabetes. In vitro, the probe increased fluorescence signal from baseline in cells expressing the β cell marker GLP-1R compared with no signal increase in GLP-1R-negative cells. In mice, the agent localized to pancreatic β cells and could be used to measure β cell mass and β cell loss. Next steps include studies to evaluate probe toxicity. Byetta exenatide, a synthetic exendin-4 from Amylin Pharmaceuticals Inc. and Eli Lilly and Co., is marketed to treat type 2 diabetes.

SciBX 4(30); doi:10.1038/scibx.2011.865 Published online Aug. 4, 2011

Patent application filed covering use in measurement of β cell mass for endoscopic, laparoscopic and intraoperative imaging; available for licensing

Reiner, T. et al. Proc. Natl. Acad. Sci. USA; published online July 18, 2011; doi:10.1073/pnas.1109859108 Contact: Ralph Weissleder, Harvard Medical School, Boston, Mass. e-mail: rweissleder@mgh.harvard.edu Contact: Diane Mathis, same affiliation as above e-mail: dm@hms.harvard.edu

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 16

ThE dISTILLERy

This week in techniques (continued)

Approach Summary Licensing statusPublication and contact information

Noninvasive, live imaging of immune responses

Noninvasive, real-time imaging of immune responses could help evaluate transplant outcomes and response to therapy. In immunocompetent mice with GFP-labeled T cells, the imaging method showed a T cell–mediated allorejection response against islet cells transplanted in the eye. The approach was used to make 3D, time-lapse recordings of T cell infiltration into the intraocular graft and also showed that the response could be reversed with a small molecule antagonist of CC chemokine receptor 5 (CCR5; CD195) and CXC chemokine receptor 3 (CXCR3). Next steps could include applying the imaging technique to humanized mice and adapting it for in vivo drug screening studies.

SciBX 4(30); doi:10.1038/scibx.2011.866 Published online Aug. 4, 2011

Patent application filed covering noninvasive imaging methods for type 1 diabetes; licensing status unavailable

Abdulreda, M.H. et al. Proc. Natl. Acad. Sci. USA; published online July 18, 2011; doi:10.1073/pnas.1105002108 Contact: Per-Olof Berggren, Karolinska Institute, Stockholm, Sweden e-mail: per-olof.berggren@ki.se Contact: Antonello Pileggi, University of Miami, Miami, Fla. e-mail: apileggi@med.miami.edu Contact: Alejandro Caicedo, same affiliation as above e-mail: acaicedo@med.miami.edu

INdEXES

Company and institution index

AAcetylon Pharmaceuticals Inc. 13Agios Pharmaceuticals Inc. 4Amgen Inc. 13Amylin Pharmaceuticals Inc. 15Atlas Venture 7

BBayer AG 10BioPontis Alliance LLC 7Brigham and Women’s hospital 5Bristol-Myers Squibb Co. 11Broad Institute of MIT and harvard 5

CChildren’s hospital Boston 1Columbia University 7Constellation Pharmaceuticals Inc. 2

Ddana-farber Cancer Institute 1,5

EEli Lilly and Co. 15EMC microcollections Gmbh 12EpiTherapeutics ApS 1Epizyme Inc. 1

Hharvard Medical School 1,4harvard University 4,5hepregen Corp. 5humabs BioMed S.A. 12

IIndex Ventures 7Institute for Research in Biomedicine 12

JJohnson & Johnson 7,12

Kkarus Therapeutics Ltd. 13

MMassachusetts Institute of Technology 4,5Memorial Sloan-kettering Cancer Center 7Merck & Co. Inc. 7,11

NNew york University 7Novartis AG 15

PPerelman School of Medicine at the University of Pennsylvania 8Pfizer Inc. 7,12Pharmos Corp. 13PureTech Ventures 7

SSangamo BioSciences Inc. 15Stanford University 15SuperGen Inc. 10

TTaconic farms Inc. 5,8

UUniversity of Copenhagen 3University of florida 7

University of North Carolina at Chapel hill 7University of Pennsylvania 7University of Virginia 7

WWhitehead Institute for Biomedical Research 4

Target and compound index

1,4-Naphthoquinone 122-Aminoquinoline 134CMenB 155-fluorouracil 11

Aα-ketoglutarate 4aβ 13Acetaminophen 5ACy-1215 13AML1-ETO oncogenic fusion protein 9AT7519 10

Bβ-Amyloid 13β-Site APP-cleaving enzyme 1 13B19 8BACE1 13BAy 1000394 10Byetta 15

CCannabinoid CB2 receptor 13Cannabinor 13

CAR 6CC chemokine receptor 5 16CC chemokine receptor 6 9CCL20 9CCR5 16CCR6 9Cd3 9Cd195 16Cd196 9Cdk1 10Cdk2 10Cdk4 10Cdk5 10Chemokine CC motif ligand 20 9Chloroquine 12Cisplatin 11c-Met proto-oncogene 15CNR2 13Constitutive androstane receptor 6Coumarin 5CXC chemokine receptor 3 16CXCR3 16Cyclin dependent kinase 5 10CyP1A2 5CyP2A6 5CyP2C 5CyP2d6 5CyP2E1 5CyP3A4 5CyP3A7 6Cytochrome P450 3A4 5

Ddebrisoquine 5diflucan 12dNM1L 14dOT1L 1dRP1 14

SciBX: Science–Business eXchange AUGUST 4, 2011 • VOLUME 4 / NUMBER 30 17

INdEXES

dynamin 1-like 14

EE1A binding protein p300 9Efavirenz 11EGfR2 8,10EP300 9EPZ004777 1ERBB2 8,10Estrogen receptor 4Exenatide 15Exendin-4 15

Ff16 12fhBP 15fluconazole 12flu-mAb 12

GGLP-1R 15GLP1R 15Glucagon-like peptide-1 receptor 15

HhA 12hdAC6 13heat shock 27 kda protein 1 13hepatocyte growth factor/ scatter factor 15

hepatoPac 6hER2 8,10hGfR 15hGf/Sf 15histone deacetylase 6 13histone methyltransferase dOT1L 1hormonally up-regulated Neu-associated kinase 8Hox 3hRX 1hSP27 13hSPB1 13hUNk 8

IIdh1 4Influenza A virus hemagglutinin 12Isocitrate dehydrogenase 1 4

KkAR3000 13kAR3166 13

LL1RE1 11LINE1 retrotransposable element 1 11

MMET 15MIP3A 9MLL 1Myeloid-lymphoid or mixed-lineage leukemia 1

NN-Acetyl-p-benzoquinone 5Neisseria meningitidis factor h–binding protein 15Neu 8,10NR1I3 6

Pp300 9Paclitaxel 10PEG 5PEG-dA 5PhGdh 4,10,11Phosphoglycerate dehydrogenase 4,10,11PkM2 4Polyethylene glycol 5Polyethylene glycol–diacrylate 5Pregnane X receptor 6Prolactin 13PRS-211,375 13Purvalanol 10PXR 6

Pyrimidinone 11Pyruvate kinase M2 isozyme 4

RRifampin 5

S(S)-2-Aminoalkyl benzimidazole 12Signal transducer and activator of transcription 3 10SMN1 13STAT3 10Survival of motor neuron 1 telomeric 13Sustiva 11

TThymidylate synthase 11Tubulin 13

ZZFn 15Zinc finger nuclease 15