Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Cancer cells exhibit increased cholesterol synthesis for membrane production.
• Cholesterol-lowering drugs (statins) are explored for cancer treatment but have dose-limiting side effects.
• Sterol 14α-demethylase (CYP51) is a downstream target in the cholesterol pathway, offering potential specificity.

Purpose of the Study:

• To identify specific inhibitors of human CYP51 for anticancer drug development.
• To overcome limitations of existing statins by targeting a more specific enzyme in cholesterol synthesis.
• To understand the molecular interactions of inhibitors with human CYP51.

Main Methods:

• Screening of commercial and experimental CYP51 inhibitors.
• Biochemical assays to measure human CYP51 inhibition.
• Cellular proliferation assays.
• X-ray crystallography of human CYP51-inhibitor complexes.

Main Results:

• Most inhibitors, including antifungals, showed weak inhibition of human CYP51.
• A novel compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), demonstrated potent inhibition.
• VFV reduced proliferation in various cancer cell types.
• Crystal structures revealed a 2:1 inhibitor/enzyme stoichiometry and provided insights into human CYP51's substrate profile and resistance to inhibition.

Conclusions:

• VFV is a promising lead compound for developing targeted anticancer therapies by inhibiting CYP51.
• Understanding human CYP51 structure-inhibitor interactions can guide the design of more potent and selective drugs.
• Targeting CYP51 offers a potentially safer alternative to systemic statin therapy for cancer.