title: Dual-Mode HDAC Prodrug for Covalent Modification and Subsequent Inhibitor Release.
abstract: Histone deacetylase inhibitors (HDACi) target abnormal epigenetic states associated with a variety of pathologies, including cancer. Here, the development of a prodrug of the canonical broad-spectrum HDACi suberoylanilide hydroxamic acid (SAHA) is described. Although hydroxamic acids are utilized universally in the development of metalloenzyme inhibitors, they are considered to be poor pharmacophores with reduced activity in vivo. We developed a prodrug of SAHA by appending a promoiety, sensitive to thiols, to the hydroxamic acid warhead (termed SAHA-TAP). After incubation of SAHA-TAP with an HDAC, the thiol of a conserved HDAC cysteine residue becomes covalently tagged with the promoiety, initiating a cascade reaction that leads to the release of SAHA. Mass spectrometry and enzyme kinetics experiments validate that the cysteine residue is covalently appended with the TAP promoiety. SAHA-TAP demonstrates cytotoxicity activity against various cancer cell lines. This strategy represents an original prodrug design with a dual mode of action for HDAC inhibition.
authors.affiliation: †Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Daniel
authors.forename: Eric D
authors.initials: ED
authors.lastname: Sullivan
authors.affiliation: †Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: †Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Chan
authors.affiliation: †Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.forename: Carol A
authors.initials: CA
authors.lastname: Fierke
authors.affiliation: †Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011355:Prodrugs; D012097:Repressor Proteins; D000077337:Vorinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases