title: 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 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.
authors.affiliation: School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology , Atlanta, Georgia, 30332-0400, United States.
authors.forename: Berkley E
authors.initials: BE
authors.lastname: Gryder
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rood
authors.forename: Kenyetta A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Vishal
authors.initials: V
authors.lastname: Patil
authors.forename: Eric D
authors.initials: ED
authors.lastname: Raftery
authors.forename: Li-Pan D
authors.initials: LP
authors.lastname: Yao
authors.forename: Marcie
authors.initials: M
authors.lastname: Rice
authors.forename: Bahareh
authors.initials: B
authors.lastname: Azizi
authors.forename: Donald F
authors.initials: DF
authors.lastname: Doyle
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D055808:Drug Discovery; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D011960:Receptors, Estrogen / Q000819:agonists / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D056572:Histone Deacetylase Inhibitors; D011960:Receptors, Estrogen