Reference Detail

Ref Type

Journal Article

PMID

(17363489)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	6	3	2007 Mar	945-56	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Rucaparib	Rucaparib	24	24

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Rucaparib	Rubraca	AG014699\|PF-01367338\|CO-388\|AG14447	PARP Inhibitor (Pan) 30	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 maintenance therapy in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer harboring a deleterious BRCA mutation, and for treatment in patients with metastatic castration-resistant prostate cancer harboring a deleterious BRCA mutation (germline and/or somatic) 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