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'Undruggable' mutation meets its match
Date:11/20/2013

argeting mutant Ras genes, the National Cancer Institute (NCI) recently emphasized the continued importance of this elusive drug target by announcing a focused $10 million effort, dubbed the RAS project, to bring together researchers to develop new ideas for blocking Ras. The project aims to spur development of new drugs or therapies to benefit patients with cancer.

Shokat's HHMI team, which is not part of the NCI initiative, started working on Ras in earnest about six years ago. Using their expertise in chemistry, Shokat and two team members -- Ulf Peters, a postdoctoral fellow, and Jonathan Ostrem, an MD-PhD student -- sketched out some early ideas for a new class of drugs that inhibit Ras mutants. "Some of the early strategies did not work," he said.

"We had to develop a new kind of screen and that ultimately led to progress in developing this new inhibitor." Shokat says they did a few things differently when defining the scope of their attack. They kept their focus narrow, being mindful of strategies that had not worked for other scientists. They also chose to study a type of K-Ras mutant called G12C (for Glycine-12 to Cysteine), a K-Ras mutant prevalent in about seven percent of patients with lung cancer. (The K-Ras gene is mutated in 20 percent of lung cancer cases, and G12C is the most frequent mutation of K-Ras.)

This mutation causes a substitution of the amino acid cysteine for glycine at position 12 in the K-Ras protein. Importantly, this cysteine sits in a location critical for the normal function of Ras. In another departure from previous efforts, Shokat and his colleagues did not try to target versions of Ras that had mutations in the amino acids aspartate and valine which are relatively common and hence where a lot of scientists had focused their attention previously. Instead, they picked G12C mutants because those Ras mutants affected a large population of lung and colorectal cancer patients (over 20,000 new patients each year in the US
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
Source:Eurekalert

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