Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity
| Autor: | Marcie Rice, Eric D. Raftery, Berkley E. Gryder, Adegboyega K. Oyelere, Michael K. Rood, Bahareh Azizi, Kenyetta A. Johnson, Vishal Patil, Donald F. Doyle, Li-Pan D. Yao |
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| Rok vydání: | 2013 |
| Předmět: |
Agonist
medicine.drug_class Estrogen receptor Antineoplastic Agents Pharmacology Article Structure-Activity Relationship Estrogen Receptor Modulators DU145 Drug Discovery medicine Animals Humans skin and connective tissue diseases Cells Cultured Estrogen receptor beta Triple-negative breast cancer Chemistry Antagonist Histone Deacetylase Inhibitors Molecular Docking Simulation Receptors Estrogen Molecular Medicine Histone deacetylase Tamoxifen medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 56:5782-5796 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 ERα and ERβ. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol-HDACi 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 (ERα 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. |
| Databáze: | OpenAIRE |
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