Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C

  • J Med Chem. 2026 Mar 12;69(5):5241-5258. doi: 10.1021/acs.jmedchem.5c02279.
Matthew L Landry  1 ,  Sushant Malhotra  1 ,  Maureen Beresini  1 ,  Connie Chan  1 ,  Emily Chan  1 ,  Cecile C de la Cruz  1 ,  Nicholas F Endres  1 ,  Marie Evangelista  1 ,  Amy Gustafson  1 ,  Dennis Hu  1 ,  Thomas Hunsaker  1 ,  Peter Hsu  1 ,  Yevgeniy Izrayelit  1 ,  Hank La  1 ,  Pablo Saenz-Lopez Larrocha  1 ,  Qihui Lian  2 ,  Mark Merchant  1 ,  Jialin Mao  1 ,  Rana Mroue  1 ,  Angela Oh  1 ,  Emile Plise  1 ,  Cheng Shao  3 ,  Michael Siu  1 ,  John C Tran  1 ,  Yanguang Wang  3 ,  Weiru Wang  1 ,  Binqing Wei  1 ,  Susan Wong  1 ,  Chun-Wan Yen  1 ,  Yuhui Zhou  1 ,  Hans E Purkey  1 ,  Timothy P Heffron  1 ,  Laurent Salphati  1
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Wuxi Apptec 288 Fu Te Zhong Lu, Wai Gaio Qiao Free Trade Zone, Shanghai 200131, P. R. China.
  • 3. Pharmaron-Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
PMID: 41769711 DOI: 10.1021/acs.jmedchem.5c02279
Abstract

Mutant KRAS is highly prevalent in human Cancer and has been actively pursued as a target for drug discovery. Much progress has been made in drugging KRAS G12C, owing to the ability of inhibitors to covalently target its oncogenic cysteine mutation at codon 12. A number of KRAS G12C inhibitors have advanced to clinical development and are being investigated for the treatment of a variety of solid tumors. Notably, many patients with KRAS G12C-positive non-small cell lung Cancer develop brain metastases. Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast Cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved.

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