title: Small molecule inhibitors of histone acetyltransferase Tip60.
abstract: Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small molecule inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small molecule inhibitors of Tip60 as mechanistic tools for functional study and as chemical leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small molecule library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compounds with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochemical studies. Further, computer modeling and kinetic assays suggest that these molecules target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chemical hits to develop further potent inhibitors for the MYST HATs.
authors.affiliation: Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.forename: Juxian
authors.initials: J
authors.lastname: Wang
authors.forename: Minyong
authors.initials: M
authors.lastname: Li
authors.forename: Yutao
authors.initials: Y
authors.lastname: Yang
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.forename: Y George
authors.initials: YG
authors.lastname: Zheng
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008958:Models, Molecular; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; C496551:Esa1 protein, S cerevisiae; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5