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|Ref Type||Journal Article|
|Authors||Thomas HD, Calabrese CR, Batey MA, Canan S, Hostomsky Z, Kyle S, Maegley KA, Newell DR, Skalitzky D, Wang LZ, Webber SE, Curtin NJ|
|Title||Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Poly(ADP-ribose) polymerase (PARP)-1 (EC 184.108.40.206) 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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Rucaparib||Rubraca||AG014699|PF-01367338|CO-388|AG14447||PARP Inhibitor (Pan) 20||Rubraca (rucaparib) binds to and inhibits PARP, which may result in accumulation of DNA damage and chemosensitization of tumor cells (PMID: 17363489). Rubraca (rucaparib) is FDA approved for use as a maintenance therapy in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, for treatment in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer harboring deleterious somatic and/or germline BRCA mutations who received 2 or more chemotherapies, and in patients with metastatic castration-resistant prostate cancer who received anti-androgen therapy and a taxane-based therapy (FDA.gov).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||colorectal cancer||not applicable||Rucaparib + Temozolomide||Preclinical - Cell line xenograft||Actionable||In a preclinical trial, Rubraca (rucaparib) sensitized colorectal cancer cell lines to Temodar (temozolomide) treatment both in culture and in cell line xenograft models (PMID: 17363489).||17363489|