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

• Published in: Molecular pharmacology 2016-09, Vol.90 (3), p.225-237
• Main Authors: Rosati, Rayna, Chen, Bailing, Patki, Mugdha, McFall, Thomas, Ou, Siyu, Heath, Elisabeth, Ratnam, Manohar, Qin, Zhihui
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Survival - drug effects; Chromatin - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytosol - drug effects; Cytosol - metabolism; Drug Design; Drug Resistance, Neoplasm - drug effects; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; HSP90 Heat-Shock Proteins - metabolism; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Ligands; Male; Models, Biological; Molecular Weight; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - chemical synthesis; Phenylthiohydantoin - chemistry; Phenylthiohydantoin - pharmacology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Proteolysis - drug effects; Receptors, Androgen - metabolism; Up-Regulation - drug effects; Vorinostat
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.116.103416

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.