2. Academic Validation
  3. Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles

Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles

  • J Am Chem Soc. 2023 Sep 20;145(37):20403-20411. doi: 10.1021/jacs.3c05899.
Zhongtang Yu 1 2 3,  Xiaoqiang He 1 2 3,  Ruiliu Wang 1 2 3,  Xinxin Xu 1 2 3,  Zhang Zhang 1 2 3,  Ke Ding 1 2 3,  Zhi-Min Zhang 1 2 3,  Yi Tan 1 2 3,  Zhengqiu Li 1 4 2 3
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 Guangzhou City Key Laboratory of Precision Chemical Drug Development, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 3 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 MOE Key Laboratory of Tumor Molecular Biology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 37534597 DOI: 10.1021/jacs.3c05899
Abstract

Owing to their remarkable pharmaceutical properties compared to those of noncovalent inhibitors, the development of targeted covalent inhibitors (TCIs) has emerged as a powerful method for Cancer treatment. The K-Ras mutant, which is prevalent in multiple cancers, has been confirmed to be a crucial drug target in the treatment of various malignancies. However, although the K-Ras(G12D) mutation is present in up to 33% of K-Ras mutations, no covalent inhibitors targeting K-Ras(G12D) have been developed to date. The relatively weak nucleophilicity of the acquired aspartic acid (12D) residue in K-Ras may be the reason for this. Herein, we present the first compound capable of covalently engaging both K-Ras(G12D) and K-Ras(G12C) mutants. Proteome profiling revealed that this compound effectively conjugates with G12C and G12D residues, modulating the protein functions in situ. These findings offer a unique pathway for the development of novel dual covalent inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159591
    K-Ras(G12D/G12C) Inhibitor
    Ras; Akt; ERK