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

Author

Listed:
  • 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
    Baylor College of Medicine)

  • Meng C. Wang

    (Baylor College of Medicine
    Baylor College of Medicine
    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
    Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • 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 , 2020. "Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17997-6
    DOI: 10.1038/s41467-020-17997-6
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    Cited by:

    1. Christoph Grohmann & Charlene M. Magtoto & Joel R. Walker & Ngee Kiat Chua & Anna Gabrielyan & Mary Hall & Simon A. Cobbold & Stephen Mieruszynski & Martin Brzozowski & Daniel S. Simpson & Hao Dong & , 2022. "Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. James Schiemer & Andrew Maxwell & Reto Horst & Shenping Liu & Daniel P. Uccello & Kris Borzilleri & Nisha Rajamohan & Matthew F. Brown & Matthew F. Calabrese, 2023. "A covalent BTK ternary complex compatible with targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Ronen Gabizon & Barr Tivon & Rambabu N. Reddi & Maxime C. M. Oetelaar & Hadar Amartely & Peter J. Cossar & Christian Ottmann & Nir London, 2023. "A simple method for developing lysine targeted covalent protein reagents," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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