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

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 (<b>CX-6</b>, <b>CX-9</b>, <b>CX-22</b>) showed nanomolar anti-CYP1B1 activity and exceptional selectivity (SI &gt; 230). In CYP1B1-overexpressing cells, the water-soluble and non-cytotoxic <b>CX-9</b> (solubility &gt; 100 μM) dose-dependently reversed docetaxel resistance, achieving efficacy at 50 μM comparable to 20 μM of the CYP1B1 inhibitor α-naphthoflavone (ANF). Molecular docking revealed similar binding modes for <b>CX-9</b> and ANF in CYP1B1’s active site. This work hints 2-(2-phenylethyl) chromones as a natural-derived scaffold for promising CYP1B1 inhibitor development.