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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Cytochrome P4501B1 (CYP1B1) is overexpressed in solid tumors, making it a potential anticancer target.
• CYP1B1 overexpression is linked to chemoresistance, reducing the efficacy of cancer drugs.
• Existing CYP1B1 inhibitors often lack scaffold diversity and selectivity, necessitating new therapeutic strategies.

Purpose of the Study:

• To identify novel scaffolds for developing selective CYP1B1 inhibitors.
• To synthesize and evaluate 2-(2-phenylethyl) chromone derivatives for anti-CYP1B1 activity.
• To investigate the potential of these compounds in overcoming docetaxel resistance.

Main Methods:

• Synthesis of 24 derivatives of 2-(2-phenylethyl) chromones.
• Structure-activity relationship (SAR) studies to determine optimal substituents.
• In vitro assays to measure CYP1B1 inhibition and selectivity.
• Cell-based assays to assess reversal of docetaxel resistance.
• Molecular docking to analyze binding interactions within the CYP1B1 active site.

Main Results:

• Identified 2-(2-phenylethyl) chromones as a novel scaffold for CYP1B1 inhibition.
• Three compounds (CX-6, CX-9, CX-22) exhibited nanomolar activity against CYP1B1 with high selectivity (SI > 230).
• Compound CX-9 demonstrated water solubility (>100 μM), non-cytotoxicity, and dose-dependently reversed docetaxel resistance in CYP1B1-overexpressing cells.
• Molecular docking indicated similar binding modes for CX-9 and the known inhibitor α-naphthoflavone (ANF) in the CYP1B1 active site.

Conclusions:

• 2-(2-phenylethyl) chromones represent a promising, natural-derived scaffold for developing selective CYP1B1 inhibitors.
• These novel inhibitors have the potential to restore drug efficacy in cancers overexpressing CYP1B1.
• Further development of this scaffold could lead to new therapeutic strategies for chemoresistant solid tumors.