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.
