Design, synthesis and biological evaluation of highly potent and selective CYP1B1 inhibitors

CYP1B1 is considered a promising target for the therapy of cancer. However, owing to the close similarity among the CYP1B1/1A1/1A2 active sites, it is challenging to discover a CYP1B1 inhibitor with both activity and selectivity considering CYP1A2 is crucial for drug metabolism whereas CYP1A1 is only abundantly expressed in specific malignancies and involved in drug metabolism. In this study, a highly potent and selective CYP1B1 inhibitor C9 was obtained by structural modification, with an inhibitory activity of 2.7 nM against CYP1B1, and more than 37037 and 7407 fold selectivity over CYP1A1 and 1A2, respectively. Furthermore, C9 effectively restored the sensitivity of Taxol to A549/Taxol cells and inhibited A549/Taxol cell migration. Molecular docking and molecular dynamics (MD) simulations showed that C9 formed necessary interactions in binding to CYP1B1 and could remain relatively stable. Taken together, C9 could be of further research as an effective and selective CYP1B1 inhibitor.