Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

• Published in: European journal of medicinal chemistry 2022-02, Vol.230, p.114088-114088, Article 114088
• Main Authors: Yang, Fang, Wen, Yalei, Wang, Chaofan, Zhou, Yuee, Zhou, Yang, Zhang, Zhi-Min, Liu, Tongzheng, Lu, Xiaoyun
• Format: Article
• Language: English
• Subjects: Anticancer; KRASG12C; PROTAC; Reversible-covalent inhibitors; Warheads
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114088

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 KRASG12C 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 KRASG12C. YF135 induces the rapid and sustained degradation of endogenous KRASG12C and attenuates pERK signaling in H358 and H23 cells in a reversible manner. The first reversible-covalent KRASG12C PROTAC YF135 was designed and synthesized. YF135 induces the rapid and sustained endogenous KRASG12C degradation and attenuates pERK signaling through the E3 ligase VHL mediated proteasome pathway. [Display omitted] •The first reversible-covalent KRASG12C PROTAC YF135 was reported.•YF135 induced the degradation of KRASG12C and decreased phospho-ERK level in H358 and H23 cells.•Mechanism study indicated that the degradation effect of YF135 on KRASG12C via E3 ligase VHL mediated proteasome pathway.