Finding potential cures in the ‘public library’

LA JOLLA, Calif.—Working from its flagship location as wellas 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 againstneurodegenerative disorders such as Alzheimer's disease.

The discovery is also notable for coming out of work thatScripps and MIT were carrying out as part of a public program to screencompounds to find potential medicines and other biologically useful molecules.Coming via the National Institutes of Health (NIH), the Common Fund MolecularLibraries Program currently funds nine screening and medicinalchemistry-related centers at academic institutions around the United States tohelp scientists find "biologically interesting molecules" independently ofcommercial laboratories.

According to Scripps, in these centers academic scientistscan test thousands of compounds at once through high-throughput screens againstvarious biological targets to "uncover 'proof-of-concept' molecules useful instudying human health and in developing new treatments for human diseases."

"Initially, the compounds in the NIH Molecular Librariesrepository were purchased from commercial sources and augmented throughchemical diversity initiatives," explains Ingrid Y. Li, director of theMolecular Libraries Program at the NIH's National Institute of Mental Health(NIMH). "In recent years, we've also encouraged academics to donatestructurally unusual compounds to add novelty to the library."

In 2008, MIT chemistry professor Dr. Gregory Fu and his labdonated a set of molecules known as aza-beta-lactams (ABLs)—molecular cousinsof penicillin and other beta-lactam antibiotics, and Fu says, "These weremolecules that probably didn't exist in commercial compound libraries, andtheir bioactivity had been virtually unexplored."

Meanwhile, Daniel Bachovchin—a graduate student in the labof Dr. Benjamin F. Cravatt III, professor and chair of the Department ofChemical Physiology at Scripps Research and a member of its Skaggs Institutefor Chemical Biology—was developing what Scripps touts as "an unusually fastand flexible" test for enzyme activity, using fluorescent molecular probes thatbind to an enzyme's active site.

Cravatt, Bachovchin and their colleagues decided to applythe new technique to the NIH compound library to find an inhibitor for anenzyme known as phosphatase methylesterase 1 (PME-1). What they found was anenantiomeric molecule, dubbed ABL127, which as Scripps puts it, "turned out tofit so precisely into a nook on PME-1 that it completely blocked PME-1 activityin cell cultures and in the brains of mice."

All of this ultimately came together into research that waspublished in early March in the journal Proceedings of the NationalAcademies of Sciences (PNAS), in the paper"Academic cross-fertilization by public screening yields a remarkable class ofprotein phosphatase methylesterase-1 inhibitors," written by Bachovchin asfirst author with contributions by Cravatt, Fu and several others.

"It was immediately clear that a single class of compoundsstood out," Bachovchin says of the research. "The fact that these compoundswork so potently and selectively in cancer cells and mice, right off thescreening deck and before we'd done any medicinal chemistry, is veryencouraging and also very unusual."

Reportedly, PME-1 has been eyed for a while as a potentialhigh-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 braincancer cells, the tumor-suppressing activity of PP2A increases, and cancerousgrowth is slowed or stopped. Researchers also have found hints that PME-1 mightplay a role in promoting Alzheimer's disease by regulating PP2A's ability todephosphorylate the Alzheimer's-associated tau protein.

"Despite its importance, no one had been able to develop aPME-1 inhibitor, mainly because standard substrate assays for the enzyme weredifficult to adapt for high-throughput screening," Cravatt says. "But webelieved that we could use our new 'substrate-free' screening technology forPME-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 arecollaborating to synthesize more ABLs and explore their chemistry, all to findthe best possible PME-1 inhibitor. The near-term goal is to use ABL127 as ascientific probe to study PME-1 functions in animals. A longer-term goal is todevelop ABL127, or related compounds, as potential oncology or Alzheimer'sdisease drugs.

Cravatt tells ddnthat while cancer and Alzheimer's may seem to be worlds apart, phosphataseproduction and inhibition have major biological impacts, "so it's notsurprising that this might influence different areas of cell biology and haveimpacts on multiple disease states."

How quickly will this research see some attention inclinical trials and be available for prescription? That's anyone's guess, asCravatt 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 academiaand industry have contacted the team about collaborating on PME-1 research.

"So our findings here are scientifically interesting, and Ithink could one day be valuable clinically," Cravatt says. "But it's importantto emphasize that we wouldn't have these findings at all, were it not for theNIH Molecular Libraries Program and its compound library. Both on the screeningside and the chemistry side, the NIH enabled us academics to bring technologiesto the table unlikely to be found in a traditional pharma setting. Ourdiscoveries thus stand as a fine example of the value of public screening forcreating novel, in-vivo activepharmacological probes for challenging protein targets."