COVER STORY
PROBING QUESTIONS A PUBLIC-PRIVATE PARTNERSHIP aims to find and share new compounds for epigenetics research LISA M. JARVIS, C&EN NORTHEAST NEWS BUREAU
colleagues’ converexpression is controlled without changes sations eventually to underlying DNA, holds great promise as led them to conduct an analysis of a new avenue for drug discovery. But the journal articles, released in 2009, to unfield has been stalled by the lack of good derstand the impact that a publicly availtool compounds—highly selective chemiable chemical probe has on biomedical cal probes that help researchers determine research (Nat. Chem. Biol., DOI: 10.1038/ the biological function of a given target. nchembio0709-436). The Structural Genomics Consortium, They discovered that when a chemical a public-private partnership set up in probe was made available without restric2004 and dedicated to open-access drug tions, a cluster of biomedical research discovery research, is trying to tackle the around its target emerged, Edwards says. probe problem and, in the process, ignite Moreover, SGC’s analysis revealed that the research around epigenetics. SGC has asonslaught of research doesn’t correlate sembled a team of researchers from industo the genetic importance of the target; try and academia to find tool compounds rather, the research is spurred simply by and make them publicly available—with no the availability of the probe. “That was a strings attached. rather striking finding,” Edwards says. “We Tool compounds don’t have the same felt these are incredibly powerful ways to qualities as a drug candidate; they don’t have open up new areas of science.” to be safe to give people or be exceptionally bioavailable. But they do need to be robust AT THE TIME, epigenetics researchers enough to inhibit or otherwise alter the acwere in desperate need of tool compounds tivity of epigenetic proteins so researchers to explore the fundamental biology of procan start to understand their function. teins. Plenty of clues implicate epigenetic “You don’t necessarily solve biology enzymes in disease, but scientists cannot problems using only biology tools—there’s thoroughly interrogate their function this whole world of chemicals out there,” without chemical probes. “There’s enough explains Michael D. Varney, senior vice smoke to know there’s a fire somewhere,” president of small-molecule drug disEdwards says, “but we don’t know what the covery at Genentech. “You have to have a biological role or therapeutic area is.” molecule that at least has a potency and SGC’s academic scientists had solved selectivity profile that many protein structures and dereally can allow you to veloped critical assays relevant interpret the results in to epigenetics, but they recogyour experiments and nized that the best tool comdraw conclusions from pounds have historically come them. That isn’t a trivial from drug companies. The most undertaking.” efficient route to finding new SGC’s efforts are probes, they decided, would be rooted in several to get medicinal chemists from years of discussions industry on board. among the nonprofit’s The problem was that indusdirector, Univertry-discovered molecules are ofsity of Toronto protein ten released with restrictions or biochemist Aled M. years after they’ve already been Edwards, and other thoroughly investigated. Comscientists about the panies hold back out of fear that impact of chemical a tool compound might one day Edwards probes. Edwards and translate into a drug candidate. COURTESY OF ALED EDWARDS
EPIGENETICS, the study of how gene
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Making it freely available could sacrifice precious intellectual property (IP). One scientist involved in the journal articles analysis was Timothy M. Willson, a medicinal chemist at GlaxoSmithKline. Willson made the case to GSK managers that the benefits of participating in a partnership with SGC outweighed the risks. By 2009 his bosses were sufficiently convinced, and SGC’s chemical probes project was launched. Edwards gives credit to GSK for buying into open access. “They took a big risk, because nobody in academia thought this would happen,”Edwards says. “GSK was a real pioneer.” Today the project has several academic collaborators and a number of pharma firms, including GSK, Abbott Laboratories, Eli Lilly & Co., Pfizer, Novartis, and Takeda Pharma ceuticals. Its resources are spread across targets to avoid duplication of efforts. Companies work individually toward finding tool compounds, but anything that is discovered goes immediately into the public domain. “The thing that makes us effective is we don’t generate any IP,” says Stephen V. Frye, director of the Center for Integrative Chemical Biology & Drug Discovery at the University of North Carolina, Chapel Hill, and a participant in SGC. “That approach just lowers the barrier so much to collaboration, because I will send our epigenetic compound to anybody.” SGC estimates each probe can cost $2 million to develop. Drug companies commit $5 million apiece to be part of the consortium and dedicate in-house medicinal chemistry efforts. SGC also has secured government grants specifically to help fund the chemical probe project. To date, Edwards says, “six or seven nice molecules,” including UNC0638, developed by Frye, and JQ1, developed by SGC and a team at Boston’s Dana-Farber Cancer Institute, have been made public, and a pipeline of projects is in the works. Although the utility of the tools remains to be seen, Edwards is enthusiastic about the progress. If even one epigenetic target is proven to be interesting because it can be validated by an SGC-generated tool compound, “it’ll cause a tsunami of people to work on it,” he says. ◾
