Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity

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• 作者：Berkley E. Gryder ; Michael K. Rood ; Kenyetta A. Johnson ; Vishal Patil ; Eric D. Raftery ; Li-Pan D. Yao ; Marcie Rice ; Bahareh Azizi ; Donald F. Doyle ; Adegboyega K. Oyelere
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5782-5796
• 全文大小：835K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

We describe a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations and either agonize or antagonize ER伪 and ER尾. The ER antagonist activities of tamoxifen鈥揌DACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol鈥揌DACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ER伪 positive breast cancer) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer), or Vero (noncancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working toward a higher therapeutic index at the earliest stages of drug development.