2. Academic Validation
  3. 143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models

143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models

  • Acta Pharmacol Sin. 2023 Jul;44(7):1475-1486. doi: 10.1038/s41401-023-01053-2.
Lan-Song Xu 1 2 3 4,  Su-Xin Zheng 5,  Liang-He Mei 6,  Ke-Xin Yang 3 4,  Ya-Fang Wang 3 4,  Qiang Zhou 6,  Xiang-Tai Kong 2,  Ming-Yue Zheng 7 8,  Hua-Liang Jiang 1 2 3 4 9,  Cheng-Ying Xie 10 11 12 13
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 2 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Suzhou AlphaMa Biotechnology Co., Ltd., Suzhou, 215123, China.
  • 6 Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, 215123, China.
  • 7 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. myzheng@simm.ac.cn.
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. myzheng@simm.ac.cn.
  • 9 Lingang Laboratory, Shanghai, 200031, China.
  • 10 Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. xiecy@lglab.ac.cn.
  • 11 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. xiecy@lglab.ac.cn.
  • 12 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. xiecy@lglab.ac.cn.
  • 13 Lingang Laboratory, Shanghai, 200031, China. xiecy@lglab.ac.cn.
PMID: 36725884 DOI: 10.1038/s41401-023-01053-2
Abstract

The KRASG12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRASG12C-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRASG12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRASG12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRASG12C mutation. 143D selectively inhibited cell proliferation and induced G1-phase cell cycle arrest and Apoptosis by downregulating KRASG12C-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (Cmax) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRASG12C-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRASG12C mutation.

Keywords

143D; KRASG12C; MAPK signaling pathway; small-molecule inhibitor; synergistic effect.

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