Structure–Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells,Journal of Medicinal Chemistry

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Structure–Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-11-03 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01228
Andrew J. Robles , Shelby McCowen ₁ , Shengxin Cai , Michaels Glassman ₁ , Francisco Ruiz ₁ , Robert H. Cichewicz , Stanton F. McHardy ₁ , Susan L. Mooberry

Affiliation

Targeted therapies for ER+/PR+ and HER2-amplified breast cancers have improved patient survival, but there are no therapies for triple negative breast cancers (TNBC) that lack expression of estrogen and progesterone receptors (ER/PR), or amplification or overexpression of HER2. Gene expression profiling of TNBC has identified molecular subtypes and representative cell lines. An extract of the Texas native plant Amyris texana was found to have selective activity against MDA-MB-453 cells, a model of the luminal androgen receptor (LAR) subtype of TNBC. Bioassay-guided fractionation identified two oxazole natural products with selective activity against this cell line. Conducted analog synthesis and structure–activity relationship studies provided analogs with more potent and selective activity against two LAR subtype cell line models, culminating in the discovery of compound 30 (CIDD-0067106). Lead compounds discovered have potent and selective antiproliferative activities, and mechanisms of action studies show they inhibit the activity of the mTORC1 pathway.

中文翻译：

新的基于天然产物的二芳基恶唑的结构-活性关系具有对雄激素受体阳性乳腺癌细胞的选择性活性。

针对ER + / PR +和HER2扩增的乳腺癌的靶向疗法可改善患者生存率，但尚无针对缺乏雌激素和孕激素受体（ER / PR）表达或HER2扩增或过度表达的三阴性乳腺癌（TNBC）的疗法。TNBC的基因表达谱已鉴定出分子亚型和代表性细胞系。德克萨斯州本地植物Amyris texana的提取物被发现对MDA-MB-453细胞具有选择性活性，MDA-MB-453细胞是TNBC的管腔雄激素受体（LAR）亚型的模型。生物测定指导的分级分离鉴定出两种对这种细胞系具有选择性活性的恶唑天然产物。进行的类似物合成和结构与活性之间的关系研究为类似物提供了对两种LAR亚型细胞系模型的更强效和选择性的活性，最终发现了化合物30（CIDD-0067106）。发现的先导化合物具有有效和选择性的抗增殖活性，作用机理研究表明它们抑制了mTORC1途径的活性。

更新日期：2017-11-05

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