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Good Inhibitors Come In Twos

Researchers develop another direct inhibitor of the ‘undruggable’ cancer-associated protein K-Ras

by Stu Borman
December 9, 2013 | A version of this story appeared in Volume 91, Issue 49

Credit: Courtesy of Kenneth Westover
SML-8-73-1 (colored structure) binds covalently in the mutated K-Ras active site.
This rendition shows the Gray group’s inhibitor, SML-8-73-1 (color stick structure), binding covalently to the active site of a mutant K-Ras (ribbon structure).
Credit: Courtesy of Kenneth Westover
SML-8-73-1 (colored structure) binds covalently in the mutated K-Ras active site.

Inhibitors of the cancer-associated protein K-Ras have been scarcer than hen’s teeth. But now two groups have popped up with them virtually simultaneously. Scientists had considered mutant Ras proteins to be “undruggable” because years-long efforts had yielded no direct inhibitors. Last month, C&EN reported that Kevan M. Shokat of the University of California, San Francisco, and coworkers developed a family of inhibitors with high cancer-killing potency that link covalently to a mutant amino acid in a key mutated K-Ras protein (C&EN, Nov. 25, page 7). C&EN missed a paper that came out the same week by Nathanael S. Gray of Harvard Medical School and coworkers, which described another covalent inhibitor of the same mutated protein (Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201307387). The Gray inhibitor, called SML-8-73-1, accesses the mutated Ras’s active site more directly than do the UCSF inhibitors, but it must be administered as a precursor that cells metabolize to the active form. Gray collaborator Kenneth D. Westover of the University of Texas Southwestern Medical Center says the team’s proof-of-concept study shows that K-Ras’s active site is indeed druggable, “despite the widely held belief, decades old now, that it is not.”


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