Zhou Chuan, Fan Zisheng, Gu Yuejiao, Ge Zhiming, Tao Zhaofan, Cui Rongrong, Li Yupeng, Zhou Guizhen, Huo Ruifeng, Gao Mingshan, Wang Dan, He Wei, Zheng Mingyue, Zhang Sulin, Xu Tianfeng
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
J Med Chem. 2024 Jan 25;67(2):1147-1167. doi: 10.1021/acs.jmedchem.3c01622. Epub 2024 Jan 10.
KRAS, 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 KRAS 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 KRAS PROTACs. Mechanism studies with the representative compound demonstrated that the potent, rapid, and selective degradation of KRAS induced by was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRAS 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 appears to be promising for the development of a new chemotherapy for KRAS-driven cancers as the complementary therapeutic strategy to KRAS inhibition.
KRAS是最常见的KRAS致癌突变，是癌症治疗中一个有前景的靶点。在此，我们报告了通过连接MRTX1133类似物和VHL配体设计、合成并对一系列KRAS PROTACs进行生物学评估的过程。连接基团部分和KRAS抑制剂部分的结构修饰表明膜通透性在KRAS PROTACs的降解活性中起关键作用。对代表性化合物的机制研究表明，该化合物诱导的KRAS有效、快速且选择性的降解是通过VHL和蛋白酶体依赖性方式进行的。该化合物选择性且有效地抑制了多种KRAS突变癌细胞的生长，在小鼠体内表现出良好的药代动力学和药效学特性，并在AsPC-1异种移植小鼠模型中显示出显著的抗肿瘤疗效。作为KRAS抑制的补充治疗策略，对该化合物的进一步优化对于开发针对KRAS驱动癌症的新化疗方法似乎很有前景。
