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

## TL;DR

Researchers discovered a new class of compounds that effectively and selectively inhibit CYP1B1, a protein linked to cancer drug resistance.

## Contribution

A novel scaffold of 2-phenylethyl chromones was identified as potent and selective CYP1B1 inhibitors.

## Key findings

- Three compounds (CX-6, CX-9, CX-22) showed nanomolar anti-CYP1B1 activity with high selectivity.
- CX-9 reversed docetaxel resistance in CYP1B1-overexpressing cells at 50 μM, comparable to 20 μM of α-naphthoflavone.
- Molecular docking showed CX-9 and α-naphthoflavone bind similarly in CYP1B1’s active site.

## 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 of the CYP1B1 inhibitor α-naphthoflavone (ANF). Molecular docking revealed similar binding modes for CX-9 and ANF in CYP1B1’s active site. This work hints 2-(2-phenylethyl) chromones as a natural-derived scaffold for promising CYP1B1 inhibitor development.