Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
J Med Chem. 2023 Mar 23;66(6):4197-4214. doi: 10.1021/acs.jmedchem.3c00075. Epub 2023 Mar 10.
The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRAS- and -mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.
蛋白水解靶向嵌合体（PROTAC）分子的连接子部分在调节降解活性、靶标选择性和物理化学性质方面起着关键作用。然而，连接子结构的化学修饰如何引起 PROTAC 降解活性的显著变化的基本原理和潜在机制仍需要进一步研究。在此，我们报告了一种高效且选择性的 SOS1 PROTAC ZZ151 的设计和表征。在系统地修饰连接子的长度和组成后，我们观察到，对 ZZ151 的连接子部分的一个原子进行细微修饰，就会导致三元复合物的形成发生显著变化，从而显著影响降解活性。ZZ151 能够快速、特异地、有效地诱导 SOS1 降解；对广泛的 KRAS 突变驱动的癌细胞表现出强大的抗增殖活性；并在小鼠的 KRAS 和 -突变异种移植瘤中显示出优异的抗癌活性。ZZ151 是开发针对 KRAS 突变体的新型化疗药物的有前途的先导化合物。
