Amgen unveils its KRas covalent inhibitor AMG 510

Abstract

Drugmaker Amgen revealed the structure of AMG 510—the first covalent inhibitor of a mutant form of the cancer-target KRas to make it into human clinical trials. The molecule was disclosed at the American Chemical Society national meeting in Orlando, Florida, last week. KRas proteins relay signals for cells to grow and divide or to mature and take on specialized functions. They do this by converting guanosine triphosphate to guanosine diphosphate. Mutants of the proteins are common in many cancers. Because of their critical functions, they’ve been eyed as cancer targets for years, but the spherical protein’s landscape is as featureless as a billiard ball when in its active state, making it tough for drugmakers to find a place to slip in a compound that might muck up the protein’s inner workings. “There’s almost nowhere that a drug can stick to on that protein,” said Amgen scientist Victor Cee, who presented