title: Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells.
abstract: Histone deacetylase inhibitors (HDACIs) can disrupt the viability of prostate cancer (PCa) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein heat shock protein 90 (HSP90). However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACIs in PCa treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACI activities, to target HSP90 and AR in enzalutamide-resistant PCa cells. The potency of the new molecules, compounds 2-75 [4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide] and 1005 [(E)-3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenyl)-N-hydroxyacrylamide], as inhibitors of nuclear and cytosolic histone deacetylases was substantially lower than that of SAHA in cell-free and in situ assays. Compounds 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90, whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (compound 1005) or more potently than (compound 2-75) SAHA. Similar to SAHA, compounds 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted approximately 55 kDa HSP90 fragment. Compared with SAHA, compound 2-75 induced greater hyperacetylation of the HDAC6 substrate α-tubulin. In contrast with SAHA, neither hybrid molecule caused substantial hyperacetylation of histones H3 and H4. Compounds 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells, with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulate HSP90 and AR in enzalutamide-resistant PCa cells with weakened effects on nuclear HDACI targets.
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Rayna
authors.initials: R
authors.lastname: Rosati
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Bailing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Patki
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: McFall
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Siyu
authors.initials: S
authors.lastname: Ou
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heath
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan ratnamm@karmanos.org zqin@wayne.edu.
authors.forename: Manohar
authors.initials: M
authors.lastname: Ratnam
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Departments of Oncology (R.R., M.P., T.M., E.H., M.R.) and Pharmaceutical Sciences (B.C., S.O., Z.Q.), Wayne State University, Detroit, Michigan ratnamm@karmanos.org zqin@wayne.edu.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008954:Models, Biological; D008970:Molecular Weight; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; D000077337:Vorinostat; C540278:enzalutamide