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

Abstract

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 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (K_D = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

GRAPHIC ABSTRACT

Keywords:

• Nur77
• Benzoylhydrazone derivatives
• hepatocellular carcinoma
• molecular dynamics simulation
• antitumor activity

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Key Research and Development Program of China under Grant number 2022YFF0710803, 2022YFF0710800, the CAMS Innovation Fund for Medical Sciences (CIFMS) under Grant number 2021-I2M-1–049, the Fundamental Research Funds for the Central Universities of China under Grant number 20720180051, the National Natural Science Foundation of China under Grant number 81773600 and the CAMS Institute of Respiratory Medicine Grant for Young Scholars under Grant number 2023-ZF-10.