Unleashing the Power of Covalent Drugs for Protein Degradation

  • Med Res Rev. 2025 Jul;45(4):1045-1076. doi: 10.1002/med.22101.
Meng-Jie Fu  1  2 ,  Hang Jin  1  2 ,  Shao-Peng Wang  1  2 ,  Liang Shen  1  2 ,  Hong-Min Liu  1  2 ,  Ying Liu  3 ,  Yi-Chao Zheng  1  2 ,  Xing-Jie Dai  1  2  4
Affiliations
  • 1. Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 2. State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 3. Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4. Key Laboratory of Cardio-Cerebrovascular Drug, China Meheco Topfond Pharmaceutical Company, Zhumadian, Henan, China.
PMID: 39834319 DOI: 10.1002/med.22101
Abstract

Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including Cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 Ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered "undruggable" shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (Btk), epidermal growth factor receptor (EGFR), as well as E3 Ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (KEAP1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.

Keywords
E3 ligase ligand; PROTAC; covalent drug; molecular glue; targeted protein degradation.
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