Discovery of Furopyrimidine-Pyrazole Hybrid Compounds Targeting p53-Mdm2 Interaction as Anticancer Agents

Abstract

Inhibiting the p53-MDM2 interaction restores the function of the tumour suppressor protein, p53, and offers a promising avenue for anticancer therapies. Herein, a novel series of pyrazoline-derived compounds was developed and synthesised to serve as potential inhibitors of the p53-MDM2 interaction. Scaffold hopping was adopted via replacing the cis-imidazoline core of Nutlin-2 with a pyrazoline core, and molecular docking confirmed the binding orientation of the designed compounds at the p53-MDM2 interaction site. The antiproliferative activities of these compounds were evaluated against the NCI60 cell lines, where compounds 6c, 6d and 9d displayed the highest inhibitory activities. Subsequently, compound 6d was selected for the five-doses NCI60 cell panel assay to afford a mean GI(50) value of 8.39 mu M. Moreover, 6d significantly reduced MDM2 expression and elevated the expression of p53 in an ELISA-based assay, yielding a biochemical IC50 value of 13.8 mu M against MDM2, which was confirmed by Western blot as well. Cytotoxicity study confirmed the selectivity of 6d towards cancerous cell lines over normal cell lines. Additionally, X-ray crystallography was used to check the stereochemistry of compound 6d. These newly identified MDM2 inhibitors represent promising candidates for the development of novel targeted anticancer agents.