title: Rational design and validation of a Tip60 histone acetyltransferase inhibitor.
abstract: Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.
authors.affiliation: 1] School of Chemistry, National University of Ireland Galway, Galway, Ireland [2] Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden [3].
authors.forename: Chunxia
authors.initials: C
authors.lastname: Gao
authors.affiliation: 1] Discipline of Pathology, School of Medicine, Clinical Science Institute, Costello Road, National University of Ireland Galway, Galway, Ireland [2].
authors.forename: Emer
authors.initials: E
authors.lastname: Bourke
authors.affiliation: 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden [2].
authors.forename: Martin
authors.initials: M
authors.lastname: Scobie
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Melina Arcos
authors.initials: MA
authors.lastname: Famme
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Koolmeister
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: 1] School of Chemistry, National University of Ireland Galway, Galway, Ireland [2] Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden [3].
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Noel F
authors.initials: NF
authors.lastname: Lowndes
authors.affiliation: 1] Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland [2] [3].
authors.forename: James A L
authors.initials: JA
authors.lastname: Brown
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008956:Models, Chemical; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5