title: Novel histone deacetylase 8 ligands without a zinc chelating group: exploring an 'upside-down' binding pose.
abstract: A novel series of HDAC8 inhibitors without a zinc-chelating hydroxamic acid moiety is reported. Photoaffinity labeling and molecular modeling studies suggest that these ligands are likely to bind in an 'upside-down' fashion in a secondary binding site proximal to the main catalytic site. The most potent ligand in the series exhibits an IC(50) of 28 μM for HDAC8 and is found to inhibit the deacetylation of H4 but not α-tubulin in SH-SY5Y cell line.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Aditya Sudheer
authors.initials: AS
authors.lastname: Vaidya
authors.forename: Raghupathi
authors.initials: R
authors.lastname: Neelarapu
authors.forename: Antonett
authors.initials: A
authors.lastname: Madriaga
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.forename: Emma
authors.initials: E
authors.lastname: Mendonca
authors.forename: Hazem
authors.initials: H
authors.lastname: Abdelkarim
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Sylvie Y
authors.initials: SY
authors.lastname: Blond
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D006877:Hydroxamic Acids; D008024:Ligands; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D015032:Zinc