用于治疗去势抵抗性前列腺癌的核雄激素受体小分子拮抗剂
Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.
作者信息
Johnson James K, Skoda Erin M, Zhou Jianhua, Parrinello Erica, Wang Dan, O'Malley Katherine, Eyer Benjamin R, Kazancioglu Mustafa, Eisermann Kurtis, Johnston Paul A, Nelson Joel B, Wang Zhou, Wipf Peter
机构信息
Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15232, United States.
出版信息
ACS Med Chem Lett. 2016 May 27;7(8):785-90. doi: 10.1021/acsmedchemlett.6b00186. eCollection 2016 Aug 11.
After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.
在高通量筛选活动确定硫醚1为核雄激素受体拮抗剂后，为了构效关系（SAR）研究构建了一个区域模型，并合成了类似物，在基于细胞的荧光素酶测定中进行评估。一种新型硫醚电子等排体环丙烷（1S，2R）-27，在C4-2-PSA-rl细胞的前列腺特异性抗原荧光素酶测定中显示出预期的活性增强以及结构特性（立体特异性SAR反应、不存在易氧化的硫原子、低分子量、柔性键和极性表面积数量减少以及类药性质评分），有资格作为前列腺癌药物开发的新先导结构。
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