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.