2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D

  • J Med Chem. 2024 Jan 25;67(2):1147-1167. doi: 10.1021/acs.jmedchem.3c01622.
Chuan Zhou 1,  Zisheng Fan 2 3 4,  Yuejiao Gu 1 5,  Zhiming Ge 5 6,  Zhaofan Tao 1 5,  Rongrong Cui 4,  Yupeng Li 7,  Guizhen Zhou 2 3 4,  Ruifeng Huo 8,  Mingshan Gao 1,  Dan Wang 8,  Wei He 4 9,  Mingyue Zheng 2 4 5 6,  Sulin Zhang 4,  Tianfeng Xu 1 5 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Lingang Laboratory, Shanghai 200031, China.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 7 Department of Pharmaceutical Sciences, School of Pharmacy and Border Biomedical Research Center, The University of Texas at EI Paso, EI Paso, Texas 79902, United States.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 9 Nanchang University, Nanchang 330031, China.
PMID: 38197882 DOI: 10.1021/acs.jmedchem.3c01622
Abstract

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for Cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant Cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

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