2. Academic Validation
  3. Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

  • Eur J Med Chem. 2022 Feb 15;230:114088. doi: 10.1016/j.ejmech.2021.114088.
Fang Yang 1,  Yalei Wen 1,  Chaofan Wang 1,  Yuee Zhou 1,  Yang Zhou 1,  Zhi-Min Zhang 1,  Tongzheng Liu 2,  Xiaoyun Lu 3
Affiliations

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 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.

Keywords

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

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