Rucaparib - CAS 459868-92-9
Catalog number: 459868-92-9
Category: Inhibitor
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Rucaparib, also known as (AG-14699 or PF-01367338, is a tricyclic indole poly(ADP-Ribose) polymerase (PARP1) inhibitor with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Rucaparib selectively binds to PARP1 and inhibits PARP1-mediated DNA repair, thereby enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapy and radiation therapy. PARP1 catalyzes post-translational ADP-ribosylation of nuclear proteins and is activated by single-strand DNA (ssDNA) breaks.
Light yellow solid powder
AG-14699 (as phosphate salt), AG-014447 (as free base); PF-01367338; AG 14699 (as phosphate salt), AG 014447 (as free base); PF 01367338; AG14699 (as phosphate salt), AG014447 (as free base); PF01367338
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1.Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo?
Ali M;Telfer BA;McCrudden C;O'Rourke M;Thomas HD;Kamjoo M;Kyle S;Robson T;Shaw C;Hirst DG;Curtin NJ;Williams KJ Clin Cancer Res. 2009 Oct 1;15(19):6106-12. doi: 10.1158/1078-0432.CCR-09-0398. Epub 2009 Sep 29.
PURPOSE: ;Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application.;EXPERIMENTAL DESIGN: ;Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition.;RESULTS: ;AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg).
2.Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial.
Thomas HD;Calabrese CR;Batey MA;Canan S;Hostomsky Z;Kyle S;Maegley KA;Newell DR;Skalitzky D;Wang LZ;Webber SE;Curtin NJ Mol Cancer Ther. 2007 Mar;6(3):945-56.
Poly(ADP-ribose) polymerase (PARP)-1 (EC 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.
3.Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer.
Dockery LE;Gunderson CC;Moore KN Onco Targets Ther. 2017 Jun 19;10:3029-3037. doi: 10.2147/OTT.S114714. eCollection 2017.
Rucaparib camsylate (CO-338, AG-014699, PF-01367338) is a potent PARP-1, PARP-2, and PARP-3 inhibitor. Phase I and II studies demonstrated clinical efficacy in both ;BRCA;-mutated (inclusive of germline and somatic) ovarian tumors and ovarian tumors with homologous recombination deficiency (HRD) loss of heterozygosity (LOH). Rucaparib has received the US Food and Drug Administration (FDA) approval for patients with deleterious ;BRCA; mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. There is evidence to suggest that rucaparib has clinical efficacy against ovarian tumors with high HRD-LOH. Rucaparib's companion diagnostic FoundationFocus™ CDx ;BRCA; test is the first FDA-approved next-generation sequencing-based companion diagnostic test designed to identify patients likely to respond to rucaparib. This article reviews the mechanisms of action, safety, approval, and indications for use of the PARP inhibitor rucaparib as well as future trials and use of rucaparib's companion diagnostic test.
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CAS 459868-92-9 Rucaparib

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