生物活性

• 靶点	PARP1 Ki:1.4nM

• 描述PARP1, also called as Poly (ADP-ribose) polymerase, is involved in the signaling of DNA damage. It can recognize and bind DNA single or double-strand breaks, thus possessing various cellular function, including regulation of apoptosis and chromosome stability, gene amplification and transcription, as well as cell division and differentiation. Rucaparib Phosphate is a potent PARP inhibitor with Ki value of 1.4 nM (measured by enzyme assays)^[1]. Rucaparib Phosphate at dose ranging in 1-10 μM can suppress the level of PAR, as well as induce γ-H2AX, formation and PARP cleavage in a dose-dependent manner indicative of DNA damage and apoptosis, respectively, in MDA-MB468, MDA-MB-231, and Cal-51 cells in the presence of 5% FBS-supplemented DMEM medium for 72 h. Rucaparib Phosphate at concentrations >2.5 μM decreased the p-Stat3 in MDA-MB-468 and MDA-MB-231, as well as dose-dependently increased the p-Akt-S473 in MDA-MB-468 and Cal-51 cells^[2]. Rucaparib Phosphate can chemosensitize neuroblastoma cell lines to temozolomide or topotecan in vitro and in vivo. Rucaparib Phosphate at concentration of 0.4 μM caused a significant sensitization of topotecan (1-30 nM) and temozolomide (1-200 μM) in NB-1691, SH-SY-5Y and SKNBE(2c) cells. Rucaparib Phosphate (1 mg/kg) increased the temozolomide-induced (68 mg/kg) tumor growth delay by 50% (to >89 days) and complete and increased the number of mice with complete and persistent tumor regressions (‎≥ 100 days). Co-administration of Rucaparib Phosphate (1 mg/kg) with topotecan (1 mg/kg) increased total number of complete regressions^[3].
• 作用机制Rucaparib Phosphate can compete with NAD⁺ for the PARP catalytic site^[4]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780	-	Growth Inhibition Assay	-	IC50=3.94 ± 0.25 μM	23729402
  A549	400 nM	Growth Inhibition Assay	24 h	increases cellular radiosensitivity	24411611
  AU565	500 nM	Growth Inhibition Assay	10–15 d	reduces cell growth in the four lines and significantly	25128455

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• 动物研究
  剂量	Mice: 2 mg/kg - 150 mg/kg[5] (p.o.), 0.05 mg/kg - 10 mg/kg[1] (i.p.) Rat: 15 mg/kg[5] (i.v.)
  给药途径	p.o., i.p., i.v.
  动物药代数据	Animal Mice[5] Rats[5] Dogs[5] Monkeys[5] Dose 15 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg Administration p.o. i.v. i.v. i.v. AUC0→inf 718 ng·h/ml Vd 6.5 L/kg 15.2 L/kg 7.2 L/kg T1/2 2.93 h 3.5 h 4.5 h 5.2 h Vz/F 88300 ml/kg CL 45.3 ml/min/kg 61.8 ml/min/kg 33.8 ml/min/kg Cmax 173 ng/ml AUC0→∞ 5.7 μg·h/ml 4.1 μg·h/ml 7.4 μg·h/ml CL/F 20900 ml/h/kg AUC0→t 682 ng·h/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03442556	ATM Gene Mutation ... more >> BRCA1 Gene Mutation BRCA2 Gene Mutation Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Homologous Recombination Deficiency Prostate Carcinoma Metastatic in the Bone PSA Level Greater Than or Equal to Two PSA Progression Stage IV Prostate Adenocarcinoma AJCC v7 Collapse <<	Phase 2	Recruiting	May 15, 2024	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Heather H. Cheng    206-606-1406    hhcheng@uw.edu    Principal Investigator: Heather H. Cheng Collapse <<
  NCT03552471	BRCA1 Gene Mutation ... more >> BRCA2 Gene Mutation Folate Receptor Alpha Positive Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Recurrent Uterine Corpus Carcinoma Recurrent Uterine Serous Carcinoma Recurrent Uterine Carcinosarcoma Platinum Resistant Ovarian Cancer Collapse <<	Phase 1	Recruiting	August 29, 2021	United States, Ohio ... more >> Ohio State University Comprehensive Cancer Center Recruiting Columbus, Ohio, United States, 43210 Contact: Floor Backes, MD    614-293-3873       Principal Investigator: Floor Backes Collapse <<

• 参考文献

• [1] Thomas HD, Calabrese CR, et al. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol Cancer Ther. 2007 Mar;6(3):945-56.

  [2] Chuang HC, Kapuriya N, et al. Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells. Breast Cancer Res Treat. 2012 Jul;134(2):649-59.

  [3] Daniel RA, Rozanska AL, et al. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res. 2009 Feb 15;15(4):1241-9.

  [4] Javle M, Curtin NJ, et al. The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy. Ther Adv Med Oncol. 2011 Nov;3(6):257-67.

  [5] RUBRACA

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