| Autor: |
Lv, Yan, Yang, Zixuan, Chen, Yiming, Ma, Xuepei, Guo, Mengqi, Zhang, Chengwei, Jiang, Xiaolin, Wang, Chengli, Li, Zhuoyue, Tai, Zhengfu, Wang, Xiao, Zhang, Siqi, Ma, Shumin, Qin, Chong |
| Zdroj: |
Journal of Medicinal Chemistry; February 2024, Vol. 67 Issue: 4 p2487-2511, 25p |
| Abstrakt: |
AMG510, as the first approved inhibitor for KRASG12Cmutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12Cmutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12Cmutant cells in vitroand in vivo. Our findings demonstrated that KRASG12Cinhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12Cinhibitor. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
