Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

Fang Yang; Yalei Wen; Chaofan Wang; Yuee Zhou; Yang Zhou; Zhi-Min Zhang; Tongzheng Liu; Xiaoyun Lu

doi:10.1016/j.ejmech.2021.114088

Efficient targeted oncogenic KRAS^G12C degradation via first reversible-covalent PROTAC

Eur J Med Chem. 2022 Feb 15:230:114088. doi: 10.1016/j.ejmech.2021.114088. Epub 2022 Jan 3.

Authors

Fang Yang¹, Yalei Wen¹, Chaofan Wang¹, Yuee Zhou¹, Yang Zhou¹, Zhi-Min Zhang¹, Tongzheng Liu², Xiaoyun Lu³

Affiliations

¹ College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
² College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: liutongzheng@jnu.edu.cn.
³ College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.

PMID: 35007863
DOI: 10.1016/j.ejmech.2021.114088

Abstract

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^G12C 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^G12C. YF135 induces the rapid and sustained degradation of endogenous KRAS^G12C and attenuates pERK signaling in H358 and H23 cells in a reversible manner.

Keywords: Anticancer; KRAS(G12C); PROTAC; Reversible-covalent inhibitors; Warheads.

MeSH terms

Carcinogenesis
Humans
Mutation
Neoplasms* / drug therapy
Neoplasms* / genetics
Oligopeptides / pharmacology*
Oncogenes
Proto-Oncogene Proteins p21(ras)* / genetics

Substances

KRAS protein, human
Oligopeptides
Proto-Oncogene Proteins p21(ras)