Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design
Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design
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DOI：
10.1194/jlr.m069229
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发表时间：
2016-08-01
影响因子：
6.5
通讯作者：
Lepesheva, Galina I.
中科院分区：
文献类型：
--
作者：
Hargrove, Tatiana Y.;Friggeri, Laura;Lepesheva, Galina I.
迅速繁殖的癌细胞会合成更多的胆固醇来构建它们的细胞膜。降胆固醇药物（他汀类药物）目前正处于抗癌化疗的临床试验中。然而，在高剂量下，他汀类药物会抑制甲羟戊酸衍生的其他重要生物分子的形成，从而导致严重的副作用。甾醇14 α -去甲基化酶（CYP51）作用于下游10步，可能是一个更具体的药物靶点，因为该途径的这一部分完全致力于胆固醇的产生。然而，筛选各种商业和实验抑制剂的微生物CYP51同源物显示，大多数（包括所有临床抗真菌药）弱抑制人CYP51活性，即使它们显示出高的表观光谱结合亲和力。仅鉴定出一种相对有效的化合物(R)- n -（1-（3,4′-二氟联苯-4-基）-2-（1h -咪唑-1-基）乙基）-4-（5-苯基-1,3,4-恶二唑-2-基）苯酰胺（VFV）。VFV已经在细胞实验中进行了进一步的测试，发现它可以减少不同类型癌细胞的增殖。（jlr）人类CYP51- vfv复合物（2.0和2.5埃）的晶体结构都显示出2:1的抑制剂/酶化学比，提供了关于更广泛的底物谱、更快的催化和更弱的人类CYP51对抑制的易感性的分子见解，并为开发更有效的抑制剂指明了方向。——哈格罗夫，t.y.， L.弗里格里，Z.瓦夫扎克，S.西瓦库马兰，E. M.亚兹洛维茨卡娅，S. W.希尔伯特，F. P. Guengerich， M. R.沃特曼，G. I.莱佩舍娃。人甾醇14 α -去甲基化酶作为抗癌化疗的靶点：走向结构辅助药物设计。
Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anti-cancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14 alpha-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.(jlr) The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 angstrom) 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 14 alpha-demethylase as a target for anticancer chemotherapy:towards structure-aided drug design.