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First Hit For A Cancer Target

Drug Discovery: Academic collaboration leads to nanomolar inhibitor for phosphatase methylesterase-1

by Sarah Everts
March 14, 2011 | A version of this story appeared in Volume 89, Issue 11

Mode of Action
PME-1 catalyzes demethylation of structure (red) at C-terminus of the enzyme PP2A, shown schematically. Inhibitor of PME-1 suppress the reaction."TPDYF" represents five C-terminal amino acids.
PME-1 catalyzes demethylation of structure (red) at C-terminus of the enzyme PP2A, shown schematically. Inhibitor of PME-1 suppress the reaction."TPDYF" represents five C-terminal amino acids.

The enzyme phosphatase methylesterase-1 (PME-1) has roles in cancer and neurodegeneration, but drug companies have not been able to target it with inhibitors because no high-throughput assays were available to measure its inhibition.

Now, a team of researchers led by Benjamin Cravatt at Scripps Research Institute in La Jolla, Calif., and Gregory Fu at Massachusetts Institute of Technology has developed a high-throughput assay for PME-1 and is reporting potent aza-β-lactam inhibitors for the target (Proc. Nat. Acad. Sci. USA, DOI: 10.1073/pnas.1015248108). Cravatt believes the procedure can be modified to make it applicable to high-throughput screening of other elusive drug targets as well.

PME-1 normally plucks methyl groups off the carboxyl terminus of a protein called PP2A. Preventing this demethylation helps suppress tumor formation, which makes PME-1 a possible anticancer target, Cravatt explains. His team developed a "creative" high-throughput assay that reports binding in the active site by means of fluorescence polarization, comments Eric Brown, who established a high-throughput screening center at McMaster University in Hamilton, Canada. "This sort of fluorescence approach is amenable to very high throughput screening and made it possible to screen an otherwise unscreenable target for molecules that compete with the fluorescence probe and are inhibitors of the enzyme," Brown adds.

With the PME-1 screen in place, Cravatt's team searched through the National Institutes of Health's compound library and hit upon aza-β-lactams that inhibit PME-1 with 10-nanomolar potency. The compounds had been submitted to the library by Fu, who prepared the chemicals for use in synthetic chemistry method development. "Chiral aza-β-lactams are not found in any commercial libraries to my knowledge and occupy a rather unique place in chemical space," Cravatt says.

"This story is amazing because a highly potent, selective, and cell-penetrant small molecule for an interesting biological target was identified from a high-throughput screen without any further medicinal chemistry optimization," comments Nathanael Gray, a chemical biologist at Harvard Medical School, in Cambridge, Mass. "Many stars had to be aligned to make this happen, perhaps most notably the inclusion in the library of aza-lactams that were synthesized for completely different reasons."

Submitting interesting molecules developed in synthetic chemistry labs to chemical libraries is becoming more common but is "not yet business as usual," says Jeff Aubé, a synthetic chemist at the University of Kansas. "This is a great example of the kinds of things that can come about by placing your compounds in the NIH screening library. Exciting chemical diversity is going untapped" for medicinal purposes when "synthetic chemists make interesting molecules but leave them on the shelf instead."

So far two pharmaceutical companies have contacted Cravatt about the new target, and he hopes to expand the new assay to other enzymes.



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