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Finding potential cures in the ‘public library’
April 2011
by Jeffrey Bouley  |  Email the author


LA JOLLA, Calif.—Working from its flagship location as well as its newer Jupiter, Fla.-based facility, the Scripps Research Institute has, in collaboration with the Massachusetts Institute of Technology (MIT), discovered a class of potential anti-cancer compounds that the researchers call "extremely potent" and which they say also seem to have potential activity against neurodegenerative disorders such as Alzheimer's disease.
The discovery is also notable for coming out of work that Scripps and MIT were carrying out as part of a public program to screen compounds to find potential medicines and other biologically useful molecules. Coming via the National Institutes of Health (NIH), the Common Fund Molecular Libraries Program currently funds nine screening and medicinal chemistry-related centers at academic institutions around the United States to help scientists find "biologically interesting molecules" independently of commercial laboratories.  
According to Scripps, in these centers academic scientists can test thousands of compounds at once through high-throughput screens against various biological targets to "uncover 'proof-of-concept' molecules useful in studying human health and in developing new treatments for human diseases."
"Initially, the compounds in the NIH Molecular Libraries repository were purchased from commercial sources and augmented through chemical diversity initiatives," explains Ingrid Y. Li, director of the Molecular Libraries Program at the NIH's National Institute of Mental Health (NIMH). "In recent years, we've also encouraged academics to donate structurally unusual compounds to add novelty to the library."  
In 2008, MIT chemistry professor Dr. Gregory Fu and his lab donated a set of molecules known as aza-beta-lactams (ABLs)—molecular cousins of penicillin and other beta-lactam antibiotics, and Fu says, "These were molecules that probably didn't exist in commercial compound libraries, and their bioactivity had been virtually unexplored."  
Meanwhile, Daniel Bachovchin—a graduate student in the lab of Dr. Benjamin F. Cravatt III, professor and chair of the Department of Chemical Physiology at Scripps Research and a member of its Skaggs Institute for Chemical Biology—was developing what Scripps touts as "an unusually fast and flexible" test for enzyme activity, using fluorescent molecular probes that bind to an enzyme's active site.  
Cravatt, Bachovchin and their colleagues decided to apply the new technique to the NIH compound library to find an inhibitor for an enzyme known as phosphatase methylesterase 1 (PME-1). What they found was an enantiomeric molecule, dubbed ABL127, which as Scripps puts it, "turned out to fit so precisely into a nook on PME-1 that it completely blocked PME-1 activity in cell cultures and in the brains of mice."  
All of this ultimately came together into research that was published in early March in the journal Proceedings of the National Academies of Sciences (PNAS), in the paper "Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors," written by Bachovchin as first author with contributions by Cravatt, Fu and several others.
"It was immediately clear that a single class of compounds stood out," Bachovchin says of the research. "The fact that these compounds work so potently and selectively in cancer cells and mice, right off the screening deck and before we'd done any medicinal chemistry, is very encouraging and also very unusual."  
Reportedly, PME-1 has been eyed for a while as a potential high-value drug target, as it chemically modifies a growth-slowing enzyme, PP2A, in a way that negates PP2A's ability to serve as a tumor suppressor. Studies have shown that when PME-1 production is reduced in some kinds of brain cancer cells, the tumor-suppressing activity of PP2A increases, and cancerous growth is slowed or stopped. Researchers also have found hints that PME-1 might play a role in promoting Alzheimer's disease by regulating PP2A's ability to dephosphorylate the Alzheimer's-associated tau protein.  
"Despite its importance, no one had been able to develop a PME-1 inhibitor, mainly because standard substrate assays for the enzyme were difficult to adapt for high-throughput screening," Cravatt says. "But we believed that we could use our new 'substrate-free' screening technology for PME-1, and we knew that we needed to try a large, high-throughput screen, because our small-scale efforts to find PME-1 inhibitors had come up empty."  
As for next steps, both the Cravatt and Fu labs are collaborating to synthesize more ABLs and explore their chemistry, all to find the best possible PME-1 inhibitor. The near-term goal is to use ABL127 as a scientific probe to study PME-1 functions in animals. A longer-term goal is to develop ABL127, or related compounds, as potential oncology or Alzheimer's disease drugs.
Cravatt tells ddn that while cancer and Alzheimer's may seem to be worlds apart, phosphatase production and inhibition have major biological impacts, "so it's not surprising that this might influence different areas of cell biology and have impacts on multiple disease states."  
How quickly will this research see some attention in clinical trials and be available for prescription? That's anyone's guess, as Cravatt emphasizes this is very early-stage research and says, half-jokingly, "We're academics, so we don't do timelines." He does note, however, that several labs from both academia and industry have contacted the team about collaborating on PME-1 research.
"So our findings here are scientifically interesting, and I think could one day be valuable clinically," Cravatt says. "But it's important to emphasize that we wouldn't have these findings at all, were it not for the NIH Molecular Libraries Program and its compound library. Both on the screening side and the chemistry side, the NIH enabled us academics to bring technologies to the table unlikely to be found in a traditional pharma setting. Our discoveries thus stand as a fine example of the value of public screening for creating novel, in-vivo active pharmacological probes for challenging protein targets."
Code: E041124



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