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Nat Rev Drug Discov. 2016 Nov;15(11):771-785. doi: 10.1038/nrd.2016.139. Epub 2016 Jul 29.

Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.

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Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.


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 this Review, we provide an in-depth analysis of the structure, dynamics, mutational activation and inactivation, and signalling mechanisms of RAS. From this perspective, we then consider potential mechanisms of action for effective RAS inhibitors. Finally, we examine each of the many recent reports of direct RAS inhibitors and discuss promising avenues for further development.

[Indexed for MEDLINE]

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