title: Targeting cancer using KAT inhibitors to mimic lethal knockouts.
abstract: Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.
authors.affiliation: Discipline of Surgery, College of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, H91 YR71, Ireland james.brown@nuigalway.ie.
authors.forename: James A L
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Discipline of Pathology, College of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, H91 YR71, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Bourke
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Goteborg, Sweden.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.affiliation: Discipline of Surgery, College of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, H91 YR71, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kerin
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5
keywords: HAT; HTATIP; KAT; Kat5; Lys-CoA; MG-149; NU9056; TH1834; Tip60; acetyltransferase; anacardic acid; bisubstrate; breast cancer; curcumin; garcinol; histone; inhibitor; lysine; pentamidine