title: Development of a histone deacetylase 6 inhibitor and its biological effects.
abstract: Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.
authors.affiliation: Department of Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Adaickapillai
authors.initials: A
authors.lastname: Mahendran
authors.forename: Yuanshan
authors.initials: Y
authors.lastname: Yao
authors.forename: Lang
authors.initials: L
authors.lastname: Ngo
authors.forename: Gisela
authors.initials: G
authors.lastname: Venta-Perez
authors.forename: Megan L
authors.initials: ML
authors.lastname: Choy
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Kim
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Ham
authors.forename: Ronald
authors.initials: R
authors.lastname: Breslow
authors.forename: Paul A
authors.initials: PA
authors.lastname: Marks
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D014199:Trehalose / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014404:Tubulin; D000077337:Vorinostat; D005047:Etoposide; D004317:Doxorubicin; D014199:Trehalose; D006655:Histone Deacetylases
keywords: anticancer agents; drug discovery; epigenetics-based chemotherapy
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