title: Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.
abstract: Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with nonsteroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone-dependent (AR+) LNCaP and to a lesser extent against hormone-independent (AR-) DU145 prostate cancer, while having greatly reduced toxicity in noncancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type-selective responses.
authors.affiliation: Parker H. Petit Institute for Bioengineering & Biosciences, Department of Chemistry and Biochemistry, Georgia Institute of Technology , 315 Ferst Dr. NW, Atlanta, Georgia 30332-0230, United States.
authors.forename: Berkley E
authors.initials: BE
authors.lastname: Gryder
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Akbashev
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rood
authors.forename: Eric D
authors.initials: ED
authors.lastname: Raftery
authors.forename: Warren M
authors.initials: WM
authors.lastname: Meyers
authors.forename: Paulette
authors.initials: P
authors.lastname: Dillard
authors.forename: Shafiq
authors.initials: S
authors.lastname: Khan
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D018613:Microscopy, Confocal; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D056572:Histone Deacetylase Inhibitors; D011944:Receptors, Androgen