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Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.


ABSTRACT: 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? and ER?. 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 (ER? 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.

SUBMITTER: Gryder BE 

PROVIDER: S-EPMC3812312 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.

Gryder Berkley E BE   Rood Michael K MK   Johnson Kenyetta A KA   Patil Vishal V   Raftery Eric D ED   Yao Li-Pan D LP   Rice Marcie M   Azizi Bahareh B   Doyle Donald F DF   Oyelere Adegboyega K AK  

Journal of medicinal chemistry 20130703 14


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) hav  ...[more]

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