Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma.

Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an essential regulator in the initiation of autophagy and represents a novel therapeutic target for colorectal cancer (CRC) treatment. Herein, we developed a series of novel ULK1 covalent inhibitors through structure-based and medicinal chemistry optimizations. Notably, compound 12i was synthesized and validated to form covalent bonds with ULK1, exhibiting pronounced selectivity and potent inhibitory activity (ULK1 IC