College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
Eur J Med Chem. 2022 Feb 15;230:114088. doi: 10.1016/j.ejmech.2021.114088. Epub 2022 Jan 3.
KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRAS with PROTAC strategy have been considered as an alternative strategy to combate cancers. However, the irreversible PROTACs may compromise the substoichiometric activity to decrease the potency. Herein, we report the development of YF135, the first reversible-covalent PROTAC capable of recruiting VHL mediated proteasomal degradation of KRAS. YF135 induces the rapid and sustained degradation of endogenous KRAS and attenuates pERK signaling in H358 and H23 cells in a reversible manner.
KRAS 是最常发生突变的致癌基因，在驱动多种癌症的发生和进展中起主要作用。用 PROTAC 策略降解致癌基因 KRAS 已被认为是对抗癌症的一种替代策略。然而，不可逆转的 PROTAC 可能会损害次化学计量活性，降低效力。在此，我们报告了 YF135 的开发，这是第一个能够招募 VHL 介导的 KRAS 蛋白酶体降解的可逆共价 PROTAC。YF135 以可逆的方式诱导内源性 KRAS 的快速和持续降解，并减弱 H358 和 H23 细胞中的 pERK 信号。
