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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.
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This content will become publicly available on August 1, 2026
Polypeptide-protein conjugation: A new paradigm for therapeutic protein delivery
Proteolysis-targeting chimera (PROTAC) has emerged as a groundbreaking therapeutic strategy by hijacking the endogenous ubiquitin proteasome system (UPS) for targeted protein degradation. These heterobifunctional molecules recruit E3 ligases to recognize the protein of interest (POI) and facilitate its ubiquitination, leading to subsequent proteasomal degradation. Compared to conventional protein inhibitors, PROTACs offer a broader range of target degradation and remain effective even against proteins with drug-resistant mutations. Moreover, PROTACs function in a catalytic manner to degrade POIs, allowing for significantly lower administration dosages. In recent years, PROTACs have shown great promise in cancer therapy due to their high efficiency and broad applicability. However, their clinical applications remain challenging due to low bioavailability, limited tumor-targeting ability, and potential side effects. Utilizing nanomedicine for the delivery of PROTACs offers a promising strategy to enhance bioavailability, improve tumor selectivity, and minimize toxicity, thereby advancing their applications in cancer treatment. In this review, we outline the fundamental design principles of PROTACs, summarize the latest progress of nanomedicines from molecular design to drug delivery for improved tumor treatment, introduce PROTAC-based combination therapies and emerging design strategies, and discuss current challenges and future prospects of PROTAC nanomedicines toward clinical translation.
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- Award ID(s):
- 2238812
- PAR ID:
- 10656389
- Publisher / Repository:
- Elsevier B.V.
- Date Published:
- Journal Name:
- Journal of Controlled Release
- Volume:
- 384
- Issue:
- C
- ISSN:
- 0168-3659
- Page Range / eLocation ID:
- 113953
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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