Design, synthesis and biological evaluation of novel (E)-α-benzylsulfonyl chalcone derivatives as potential BRAF inhibitors

Activating mutations in the BRAF serine/threonine kinase are found in more than 70% of human melanomas, >90% of which are BRAFV600E. It provides new therapeutic opportunities in malignant melanoma. In silico and in vitro screening of our compound collection has identified Hit 2 as BRAFV600E inhibitor. Based on its structure, a series of novel (E)-α-benzylsulfonyl chalcone derivatives (13–40) were designed and synthesized. Compound 38 exhibited the most potent inhibitory activity with an IC50 value of 0.17 μM for BRAFV600E and GI50 value of 0.52 μM for mutant BRAF-dependent cells. The results of cell based pERK activity and cellular selectivity suggested that those compounds could selectively inhibit proliferation of mutant BRAF-dependent melanoma cell line through inhibition of oncogenic BRAF.

Graphical abstractBased on in silico screening results, a series of novel (E)-α-benzylsulfonyl chalcone derivatives were designed and synthesized as BRAFV600E inhibitor. Among which (E)-2-(4-Chlorobenzylsulfonyl)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (38) exhibited the most potent inhibitory activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► In silico screening was introduced in this study. ► A series of novel (E)-α-benzylsulfonyl chalcones (13–40) were synthesized. ► Compound 38 exhibited the most potent inhibitory activity of BRAFV600E