Drugging all RAS isoforms with one pocket

Future Med Chem. 2020 Nov;12(21):1911-1923. doi: 10.4155/fmc-2020-0221. Epub 2020 Aug 11.

Abstract

Activating mutations in the three human RAS genes, KRAS, NRAS and HRAS, are among the most common oncogenic drivers in human cancers. Covalent KRASG12C inhibitors, which bind to the switch II pocket in the 'off state' of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRASG12C-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the 'on state' have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

Keywords: BI-2852; GTPase; KRAS; small molecule inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • ras Proteins / antagonists & inhibitors*
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • ras Proteins