2. Academic Validation
  3. Design, synthesis, and biological evaluation of death-associated protein kinase 1 PROTACs

Design, synthesis, and biological evaluation of death-associated protein kinase 1 PROTACs

  • Bioorg Chem. 2025 Oct:165:109044. doi: 10.1016/j.bioorg.2025.109044.
Xueyin Wu 1,  Ruomeng Li 2,  Wujin Tian 1,  Jing Yao 2,  Dongmei Chen 2,  Tae Ho Lee 3,  Yang Liu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, Fujian 350122, China.
  • 2 Fujian Key Laboratory of Cognitive Function and Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University (FMU), Fuzhou, Fujian 350122, China.
  • 3 Fujian Key Laboratory of Cognitive Function and Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University (FMU), Fuzhou, Fujian 350122, China. Electronic address: tlee0813@fjmu.edu.cn.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, Fujian 350122, China. Electronic address: liuyang966@163.com.
PMID: 41032954 DOI: 10.1016/j.bioorg.2025.109044
Abstract

Death-associated protein kinase 1 (DAPK1) serves as a crucial regulator of both Autophagy and Apoptosis. DAPK1 has been closely linked to Cancer and various neurodegenerative diseases. Neurodegenerative disorders are chronic and progressive conditions characterized by the gradual loss of neuronal function and structure. Despite ongoing research, no effective cure currently exists, and further studies are needed. The emerging PROteolysis TArgeting Chimeras (PROTACs) strategy, characterized by high potency and broad target coverage, may represent a promising avenue for therapeutic development. Here we describe the design, synthesis, and biological evaluation of first-in-class PROTACs targeting DAPK1. The compound with the most promising results, CP1, can achieve sustained and effective degradation of DAPK1 at a relatively low concentration (DC50 = 0.1196 μM). Overall, our compound CP1 demonstrated strong efficacy in degrading DAPK1 and shows potential for treating neuronal cell death.

Keywords

Death-associated protein kinase 1; Degradation; Neuronal cell death; PROTAC.

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