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Preclinical Evaluation of a Novel ATM Inhibitor, KU59403, In Vitro and In Vivo in p53 Functional and Dysfunctional Models of Human Cancer

Lookup NU author(s): Michael Batey, Dr Yan Zhao, Suzanne Kyle, Professor Herbie Newell, Professor Nicola Curtin

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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. (C) 2013 AACR.


Publication metadata

Author(s): Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NMB, Lau A, Newell DR, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2013

Volume: 12

Issue: 6

Pages: 959-967

Print publication date: 01/06/2013

Online publication date: 19/03/2013

Acceptance date: 22/02/2013

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1535-7163.MCT-12-0707

DOI: 10.1158/1535-7163.MCT-12-0707


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