Discovery of novel selective CYP1B1 inhibitors: Design, synthesis and biological evaluation

Cytochrome P450 1B1 (CYP1B1), a key regulator implicated in tumor drug resistance, is aberrantly overexpressed in various malignancies, including non-small cell lung Cancer (NSCLC). This study initially elucidated the correlation between CYP1B1 protein levels and paclitaxel resistance in A549 cells using techniques such as Western blotting. Subsequently, leveraging the molecular scaffold of the stilbene-type inhibitor TMS, we employed a computer-aided scaffold hopping strategy to design and synthesize 28 novel derivatives. Screening based on Ethoxyresorufin-O-deethylase (EROD) activity identified the preferred compound, B14, which exhibited a half-maximal inhibitory concentration (IC₅₀) of 6.05 ± 0.74 nM against CYP1B1. Crucially, B14 demonstrated remarkable selectivity, exceeding 1600-fold and 16,000-fold over CYP1A1 and CYP1A2, respectively. Functional studies revealed that B14 significantly enhanced paclitaxel-mediated Apoptosis and restored paclitaxel sensitivity in A549/Taxol-resistant (A549/Tax) cells. Furthermore, B14 effectively inhibited the epithelial-mesenchymal transition (EMT) process, leading to a marked reduction in the migration and invasion capabilities of A549/Tax cells. Molecular dynamics simulations disclosed that B14 forms stable π-π interactions within the active site of CYP1B1, exhibiting superior binding stability compared to TMS. Collectively, this study successfully developed a highly selective CYP1B1 inhibitor with promising research potential, offering a novel candidate compound for reversing paclitaxel resistance.

EMT; Molecular dynamics simulation; Paclitaxel-resistant; Selective CYP1B1 inhibitors; Structure activity relationships.