Development of first-in-class PROTAC degraders of TAK1

Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is a serine/threonine kinase serving as a critical signaling node in cellular responses to various inflammatory stimuli. Dysregulation of TAK1-mediated pathways is commonly associated with inflammatory diseases and cancer, rendering TAK1 a promising pharmacological target for therapeutic intervention. In this study, we report the design and development of proteolysis-targeting chimeras (PROTACs) specifically tailored to degrade TAK1, offering a novel therapeutic approach for TAK1-related diseases. Takinib-based heterobifunctional compounds 11 and 16 induced potent, proteasome-dependent TAK1 depletion in tumor necrosis factor-alpha (TNF-α)-stimulated cancer cells. In cellular assays, these PROTACs demonstrated superior efficacy over takinib and its combination with corresponding E3 ligase ligands in reducing cancer cell viability and inducing apoptosis. The TAK1 degraders presented here provide valuable tools to further investigate the biological roles of TAK1 in diverse pathological and physiological contexts.