Direct Small-Molecule Inhibitors of KRAS

From undruggable target to drug discovery on horizon

KRAS is the most frequently mutated oncogene in human cancer. In addition to holding this distinction, unsuccessful attempts to target this protein have led to the characterization of RAS as “undruggable”.

However, recent advances in technology and novel approaches to drug discovery have renewed hope that a direct KRAS inhibitor may be on the horizon.

In a review article published in the Nature Reviews Drug Discovery, Jonathan M. Ostrem of the Department of Medicine, Brigham and Women’s Hospital, Boston, MA, US and Kevan M. Shokat of the Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, US provide an in-depth analysis of the

  • structure
  • dynamics
  • mutational activation and inactivation and
  • signalling mechanisms of RAS.

From this perspective, the authors then consider potential mechanisms of action for effective RAS inhibitors.

Finally, they examine each of the many recent reports of direct RAS inhibitors and discuss promising avenues for further development.

Both authors are joint inventors on a University of California Board of Regents-owned patent application covering inhibitors of KRAS, which has been licensed to Araxes Pharma LLC. They also hold stock in and are consultants to Araxes Pharma LLC.


Jonathan M. L. Ostrem & Kevan M. Shokat. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.Nature Reviews Drug Discovery 2016; 15: 771–785. doi:10.1038/nrd.2016.139