Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial
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 tri...
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Published in | Molecular cancer therapeutics Vol. 6; no. 3; pp. 945 - 956 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.03.2007
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Subjects | |
Online Access | Get full text |
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Summary: | 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 ( K i , 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. [Mol Cancer
Ther 2007;6(3):945–56] |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-06-0552 |