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

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 and Jin Wang ()
Additional contact information
Wen-Hao Guo: Baylor College of Medicine
Xiaoli Qi: Baylor College of Medicine
Xin Yu: Baylor College of Medicine
Yang Liu: The University of Texas MD Anderson Cancer Center
Chan-I Chung: University of California−San Francisco
Fang Bai: Rice University
Xingcheng Lin: Massachusetts Institute of Technology
Dong Lu: Baylor College of Medicine
Lingfei Wang: Baylor College of Medicine
Jianwei Chen: Baylor College of Medicine
Lynn Hsiao Su: Baylor College of Medicine
Krystle J. Nomie: The University of Texas MD Anderson Cancer Center
Feng Li: Baylor College of Medicine
Meng C. Wang: Baylor College of Medicine
Xiaokun Shu: University of California−San Francisco
José N. Onuchic: Rice University
Jennifer A. Woyach: The Ohio State University
Michael L. Wang: The University of Texas MD Anderson Cancer Center
Jin Wang: Baylor College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17997-6

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