International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Guangzhou City Key Laboratory of Precision Chemical Drug Development, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
J Am Chem Soc. 2023 Sep 20;145(37):20403-20411. doi: 10.1021/jacs.3c05899. Epub 2023 Aug 3.
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 . These findings offer a unique pathway for the development of novel dual covalent inhibitors.
与非共价抑制剂相比，靶向共价抑制剂（TCIs）具有显著的药物特性，因此它已成为癌症治疗的一种强大方法。已证实，在多种癌症中普遍存在的 K-Ras 突变是治疗各种恶性肿瘤的关键药物靶点。然而，尽管 K-Ras（G12D）突变约占 K-Ras 突变的 33%，但迄今为止尚未开发出针对 K-Ras（G12D）的共价抑制剂。K-Ras 中获得的天冬氨酸（12D）残基的亲核性相对较弱可能是原因之一。在这里，我们首次展示了一种能够与 K-Ras（G12D）和 K-Ras（G12C）突变体共价结合的化合物。蛋白质组谱分析显示，该化合物可有效与 G12C 和 G12D 残基结合，调节蛋白质功能。这些发现为开发新型双重共价抑制剂提供了独特的途径。
