TY - JOUR
T1 - Human sterol 14α-demethylase as a target for anticancer chemotherapy
T2 - Towards structure-aided drug design
AU - Hargrove, Tatiana Y.
AU - Friggeri, Laura
AU - Wawrzak, Zdzislaw
AU - Sivakumaran, Suneethi
AU - Yazlovitskaya, Eugenia M.
AU - Hiebert, Scott W.
AU - Guengerich, F. Peter
AU - Waterman, Michael R.
AU - Lepesheva, Galina I.
N1 - Funding Information:
This work was supported by National Institute of General Medical Sciences Grant GM067871 (to G.I.L). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2016 by the American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/8
Y1 - 2016/8
N2 - 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. .
AB - 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. .
KW - Cholesterol
KW - Cholesterol/biosynthesis
KW - Cytochrome p450
KW - Drug therapy/hypolipidemic drugs
KW - Enzymology/enzyme mechanisms
KW - Inhibition
KW - Membranes
KW - Supplementary cancer
KW - X-ray crystallography
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U2 - 10.1194/jlr.M069229
DO - 10.1194/jlr.M069229
M3 - Article
C2 - 27313059
AN - SCOPUS:84980351351
SN - 0022-2275
VL - 57
SP - 1552
EP - 1563
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 8
ER -
