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Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial

Lookup NU author(s): Huw Thomas, Dr Christopher Calabrese, Michael Batey, Suzanne Kyle, Professor Herbie Newell, Lan Wang, Professor Nicola Curtin

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Abstract

Poly(ADP-ribose) polymerase (PARP)-1 (EC 2.4.2.30) is a nuclear enzyme that promotes the base excision repair of DNA breaks. Inhibition of PARP-1 enhances the efficacy of DNA alkylating agents, topoisomerase I poisons, and ionizing radiation. Our aim was to identify a PARP inhibitor for clinical trial from a panel of 42 potent PARP inhibitors (K1, 1.4-15.1 nmol/L) based on the quinazolinone, benzimidazole, tricyclic benzimidazole, tricyclic indole, and tricyclic indole-1-one core structures. We evaluated chemosensitization of temozolomide and topotecan using LoVo and SW620 human colorectal cells; in vitro radiosensitization was measured using LoVo cells, and the enhancement of antitumor activity of temozolomide was evaluated in mice bearing SW620 xenografts. Excellent chemopotentiation and radiopotentiation were observed in vitro, with 17 of the compounds causing a greater temozolomide and topotecan sensitization than the benchmark inhibitor AG14361 and 10 compounds were more potent radiosensitizers than AG14361. In tumor-bearing mice, none of the compounds were toxic when given alone, and the antitumor activity of the PARP inhibitor-temozolomide combinations was unrelated to toxicity. Compounds that were more potent chemosensitizers in vivo than AG14361 were also more potent in vitro, validating in vitro assays as a prescreen. These studies have identified a compound, AG14447, as a PARP inhibitor with outstanding in vivo chemosensitization potency at tolerable doses, which is at least 10 times more potent than the initial lead, AG14361. The phosphate salt of AG14447 (AG014699), which has improved aqueous solubility, has been selected for clinical trial. Copyright © 2007 American Association for Cancer Research.


Publication metadata

Author(s): Thomas HD, Calabrese CR, Batey M, Canan S, Hostomsky Z, Kyle S, Maegley K, Newell DR, Skalitzky D, Wang L, Webber SE, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2007

Volume: 6

Issue: 3

Pages: 945-956

Print publication date: 01/03/2007

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

URL: http://dx.doi.org/10.1158/1535-7163.MCT-06-0552

DOI: 10.1158/1535-7163.MCT-06-0552

PubMed id: 17363489


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