Discovery of 2-phenylethyl chromones as potent and selective CYP1B1 inhibitors.

ABSTRACT: Cytochrome P4501B1 (CYP1B1), overexpressed in solid tumours but minimally in healthy tissues, is a promising anticancer target linked to chemoresistance. While CYP1B1 inhibitors can restore drug efficacy, most suffer from limited scaffold diversity and poor selectivity against other CYPs. We identified 2-(2-phenylethyl) chromones as a novel scaffold for anti-CYP1B1 activity and synthesised 24 derivatives with varied ring A/B substituents and established the SAR. Three compounds (CX-6, CX-9, CX-22) showed nanomolar anti-CYP1B1 activity and exceptional selectivity (SI > 230). In CYP1B1-overexpressing cells, the water-soluble and non-cytotoxic CX-9 (solubility > 100 μM) dose-dependently reversed docetaxel resistance, achieving efficacy at 50 μM comparable to 20 μM

SUBMITTER: Chen W 

PROVIDER: S-EPMC12777840 | biostudies-literature | 2026 Dec

REPOSITORIES: biostudies-literature