2. Academic Validation
  3. Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z