Direct KRAS Inhibition

KRAS inhibition drug

Three-dimensional renditions of the KRAS G12C mutant protein reveal a previously unknown “binding pocket.” This discovery led to the development of a new drug capable of binding to and inhibiting the mutant KRAS protein. [Click on the image to view an enlargement.]
Image reproduced with permission from: JM Ostrem, et al. Nature 000, 1-4 (2013), doi:10.1038/nature12796

In the field of drug design, the protein KRAS is legendary. It has been on everyone’s “target” list for more than 30 years due to its status as the most commonly mutated oncogene in human cancers. Despite this high profile, KRAS has earned a reputation in scientific circles as being “undruggable” because many pharmaceutical, biotech, and academic laboratories have failed to design a drug that successfully targets the mutant gene.

Recently, however, Howard Hughes Medical Institute (HHMI) researchers at the University of California, San Francisco, identified and exploited a newfound “Achilles heel” in KRAS. The weak point is a newly discovered “pocket,” or binding site, identified by HHMI investigator and Dream Team member Kevan M. Shokat, PhD, and colleagues. Shokat and his team have designed a chemical compound that fits inside this pocket and inhibits the normal activity of mutant KRAS, but leaves the normal protein untouched.

“KRAS is considered to be the most important oncogene in cancer and is widely believed to be ‘undruggable,’” said Shokat. “We report the discovery of a new pocket on KRAS that is druggable. We believe this has real translational implications for patients.”

In a research article published November 20, 2013, in the journal Nature, Shokat’s team described a novel chemical compound that fits into a previously unknown pocket in K-Ras and interferes with function of the enzyme.

Shokat’s team started working on Ras in earnest about six years earlier. 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 KRAS mutant called G12C (for glycine-12 to cysteine), a KRAS mutant prevalent in about 7% of patients with lung cancer. (The KRAS gene is mutated in 20% of lung cancer cases, and G12C is the most frequent mutation of KRAS.)

Shokat says the presence of this cysteine conveyed certain chemical properties that gave his team a unique handle for drug design. “Everybody else [developing drug design strategies] had been thinking they had to go after all the Ras mutants,” Shokat says. “We looked for what no else had done and we picked this particular mutation because of its chemical properties.”

Over a three-year period, the team developed more than 500 chemical compounds to see if they could identify one that would bind and inhibit KRAS G12C. Their studies led to the identification of a potent and specific inhibitor of KRAS. “One of the most important aspects of this is that this small molecule inhibits only mutant KRAS and not the normal protein,” Shokat says.

Next steps include continuing to optimize this compound so that it can be further tested to see how well the compound kills cancer cells with the G12C mutation.