title: Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer.
abstract: Ataxia telangiectasia mutated (ATM) kinase signals DNA double-strand breaks (DSB) to cell-cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo- and radiosensitization. KU59403 is an ATM inhibitor with the potency, selectivity, and solubility for advanced preclinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116, and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide, and doxorubicin. Chemo- and radiosensitization by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hours in tumor xenografts. KU59403 significantly enhanced the antitumor activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were nontoxic alone and well-tolerated in combination. Chemosensitization was both dose- and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to show good tissue distribution and significant chemosensitization in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle preclinical data to support the future clinical development of ATM inhibitors.
authors.affiliation: Newcastle University, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Batey
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kyle
authors.forename: Caroline
authors.initials: C
authors.lastname: Richardson
authors.forename: Andrew
authors.initials: A
authors.lastname: Slade
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011753:Pyrones / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D006575:Heterocyclic Compounds, 3-Ring; C586451:KU59403; D011753:Pyrones; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin