数字农科院2.0

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

文献类型： 外文期刊

作者： Wenming Chen;Wenchong Ye;Yinghong Long;Ye Zhang;Wen Zhou;Wei Wang

作者机构：

关键词： Chromone derivatives;CYP1B1;resistance reversal;selectivity;synthesis

期刊名称： Journal of Enzyme Inhibition and Medicinal Chemistry

ISSN： 1475-6366

年卷期： 2026 年 41 卷 1 期

页码：

收录情况： SCIE（2025版）

摘要： 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.

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