Design, synthesis, and biological evaluation of novel GSK-3β covalent inhibitors for cancer treatment

Glycogen synthase kinase-3β (GSK-3β) has been firmly established as a validated oncogenic target, intricately linked to tumor proliferation and survival mechanisms. However, the advancement of covalent GSK-3β inhibitors has been significantly impeded by the issue of off-target toxicity, especially liver-related adverse effects that pose a major challenge to their clinical application. To address these challenges, we implemented a comprehensive strategy integrating pharmacophore fusion with a targeted covalent inhibition approach. Based on these foundations, we meticulously designed and synthesized a novel series of 1,2,4-thiadiazole-3,5-dione derivatives. Through a rigorous screening process and in-depth mechanistic investigations, we discovered that the selected compound 7f exerted its inhibitory against GSK-3β by up-regulating the expression level of phosphorylated GSK-3β (p-GSK-3β). This upregulation of p-GSK-3β led to a subsequent suppression of the expression of p-NF-κB P65 and X-linked inhibitor of Apoptosis protein (XIAP), along with key oncoproteins such as c-Myc and Cyclin D1. As a result, these molecular events induced Apoptosis and cell cycle arrest. In conclusion, our findings indicated that the selected compound 7f served as a highly promising lead compound, and this comprehensive approach demonstrated significant potential for the development of next-generation covalent GSK-3β inhibitors, which are expected to exhibit an improved therapeutic index and provide a more efficacious strategy for Cancer therapy.