Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor

J Med Chem. 2024 Jul 11;67(13):11024-11052. doi: 10.1021/acs.jmedchem.4c00572. Epub 2024 Jun 26.

Abstract

Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Proto-Oncogene Proteins p21(ras)* / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

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