Discovery of Highly Selective CYP1B1 Inhibitors

Tumor-drug resistance remains a critical challenge in pharmaceutical research. Recent studies have identified CYP1B1 as a potential target mediating paclitaxel resistance. In this study, we employed structure-based drug design to synthesize a series of thiazoleamide derivatives, leading to the identification of multiple potent and selective CYP1B1 inhibitors. Compound B20 exhibited exceptional selectivity across seven CYP isoforms, with enzymatic kinetic studies confirming its competitive inhibition mechanism. Biological evaluations demonstrated the capacity of B20 to resensitize paclitaxel-resistant cells while maintaining favorable tumor/normal cell selectivity. Furthermore, B20 significantly inhibited the migration and invasion of A549/T cells. In vitro metabolism stability parameters revealed excellent human liver microsomal stability and plasma stability. Pharmacokinetic studies in rats showed favorable parameters. Molecular dynamics simulations revealed stable binding with key residues of CYP1B1 (Phe134/Phe231/Phe268) through π-π stacking interactions. These comprehensive data position B20 as a promising compound for overcoming paclitaxel resistance via CYP1B1 inhibition.