• Home
  • Search Results
  • Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry.

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry.

Nature communications (2020-08-28)
Wen-Hao Guo, Xiaoli Qi, Xin Yu, Yang Liu, Chan-I Chung, Fang Bai, Xingcheng Lin, Dong Lu, Lingfei Wang, Jianwei Chen, Lynn Hsiao Su, Krystle J Nomie, Feng Li, Meng C Wang, Xiaokun Shu, José N Onuchic, Jennifer A Woyach, Michael L Wang, Jin Wang
ABSTRACT

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton's Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resazurin sodium salt, certified by the Biological Stain Commission