title: Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors.
abstract: In this report, we describe new HDAC inhibitors designed to exploit a unique sub-pocket in the HDAC8 active site. These compounds were based on inspection of the available HDAC8 crystal structures bound to various inhibitors, which collectively show that the HDAC8 active site is unusually malleable and can accommodate inhibitor structures that are distinct from the canonical 'zinc binding group-linker-cap group' structures of SAHA, TSA, and similar HDAC inhibitors. Some inhibitors based on this new scaffold are >100-fold selective for HDAC8 over other class I and class II HDACs with IC(50) values <1microM against HDAC8. Furthermore, treatment of human cells with the inhibitors described here shows a unique pattern of hyperacetylated proteins compared with the broad-spectrum HDAC inhibitor TSA.
authors.affiliation: Department of Chemistry, Ithaca College, Ithaca, NY 14850, USA.
authors.forename: Keris
authors.initials: K
authors.lastname: Krennhrubec
authors.forename: Brett L
authors.initials: BL
authors.lastname: Marshall
authors.forename: Mark
authors.initials: M
authors.lastname: Hedglin
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ulrich
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000077337:Vorinostat
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012097:Repressor Proteins; C012589:trichostatin A; D000077337:Vorinostat; C409470:HDAC8 protein, human; D006655:Histone Deacetylases