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

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


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Drug Design*
  • Humans
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / chemistry*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Antineoplastic Agents
  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)