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

Tatiana Y. Hargrove, Laura Friggeri, Zdzislaw Wawrzak, Suneethi Sivakumaran, Eugenia M. Yazlovitskaya, Scott W. Hiebert, F. Peter Guengerich, Michael R. Waterman, Galina I. Lepesheva*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    42 Scopus citations


    Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterollowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent 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), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors.-Hargrove, T. Y., L. Friggeri, Z. Wawrzak, S. Sivakumaran, E. M. Yazlovitskaya, S. W. Hiebert, F. P. Guengerich, M. R. Waterman, and G. I. Lepesheva. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design. .

    Original languageEnglish (US)
    Pages (from-to)1552-1563
    Number of pages12
    JournalJournal of lipid research
    Issue number8
    StatePublished - Aug 2016


    • Cholesterol
    • Cholesterol/biosynthesis
    • Cytochrome p450
    • Drug therapy/hypolipidemic drugs
    • Enzymology/enzyme mechanisms
    • Inhibition
    • Membranes
    • Supplementary cancer
    • X-ray crystallography

    ASJC Scopus subject areas

    • Endocrinology
    • Biochemistry
    • Cell Biology


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