Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported and the native ligand at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of to Nur77's Site C but not to Sites A or B. Specifically, bound strongly to Nur77-LBD ( = 445.3 nM) and could activate Nur77's transcriptional activity. Furthermore, exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.