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Scripps Research and MIT scientists discover class of potent anti-cancer compounds
Date:3/7/2011

human diseases.

"Initially the compounds in the NIH Molecular Libraries repository were purchased from commercial sources and augmented through chemical diversity initiatives," explained Ingrid Y. Li, director of the Molecular Libraries Program at the NIH 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." (See http://mli.nih.gov/mli/compound-repository/.)

In 2008, Fu's lab donated a set of molecules known as aza-beta-lactams (ABLs) molecular cousins of penicillin and other beta-lactam antibiotics. "These were molecules that probably didn't exist in commercial compound libraries, and their bioactivity had been virtually unexplored," said Fu.

Meanwhile, across the country, in the Cravatt lab at Scripps Research campus in La Jolla, California, Bachovchin was developing an unusually fast and flexible test for enzyme activity, using fluorescent molecular probes that bind to an enzyme's active site. Researchers can use such tests to measure whether an enzyme of interest loses its activity in the presence of another chemical compound. Bachovchin, Cravatt, and their colleagues decided to apply the new technique to the NIH compound library, to find an inhibitor for an enzyme known as PME-1 (phosphatase methylesterase 1).

Long seen as a potential high-value drug target, PME-1 chemically modifies a growth-slowing enzyme, known as 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 dephosphoryate the Alzheimer's-associated tau protein.

"Despite its importance, no one had been able to de
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

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