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 is a potent PARP inhibitor with Ki value of 1.4nM (measured by enzyme assays). Rucaparib at dose ranging in 1-10μM 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 72h. Rucaparib at concentrations>2.5μM 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. Rucaparib can chemosensitize neuroblastoma cell lines to temozolomide or topotecan in vitro and in vivo. Rucaparib at concentration of 0.4μM caused a significant sensitization of topotecan (1-30nM) and temozolomide (1-200μM) in NB-1691, SH-SY-5Y and SKNBE(2c) cells. Rucaparib (1mg/kg) increased the temozolomide-induced (68mg/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 (1mg/kg) with topotecan (1mg/kg) increased total number of complete regressions.

• 动物研究
  剂量	Mice: 150 mg/kg - 450 mg/kg[3] (p.o.); 0.1 mg/kg - 10 mg/kg[2] (i.p.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[4] Rats[4] Dogs[4] Monkeys[4] Dose 15 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg Administration p.o. i.v. i.v. i.v. T1/2 2.93 h 3.5 h 4.5 h 5.2 h Tmax 2.00 h 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 AUC0→inf 718 ng·h/ml Vd 6.5 L/kg 5.2 L/kg 7.2 L/kg 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

• 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
  NCT02711137	Solid Tumors	Phase 1 Phase 2	Active, not recruiting	December 2018	United States, Alabama ... more >> University of Alabama Birmingham, Alabama, United States, 35294-3300 United States, California University of California La Jolla, California, United States, 92093 United States, Colorado Sarah Cannon Research Institute at Health One Denver, Colorado, United States, 80218 United States, Connecticut Yale University New Haven, Connecticut, United States, 06510 United States, Florida Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136 Hematology - Oncology Associates of Treasure Coast Port Saint Lucie, Florida, United States, 34952 United States, Michigan University of Michigan Ann Arbor, Michigan, United States, 48109 United States, Minnesota University of Minnesota Minneapolis, Minnesota, United States, 55455 United States, Missouri Washington University Saint Louis, Missouri, United States, 63110 United States, New York University of Rochester, Wilmot Cancer Center Rochester, New York, United States, 14642 United States, North Carolina University of North Carolina at Chapel Hill Chapel Hill, North Carolina, United States, 27599 Wake Forest Baptist Health Winston-Salem, North Carolina, United States, 27157 United States, Texas Oncology Consultants, P.A. Houston, Texas, United States, 77030 The Methodist Hospital Houston, Texas, United States, 77030 United States, Utah Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 United States, Washington MultiCare Institute for Research and Innovation Tacoma, Washington, United States, 98405 Belgium Institut Jules Bordet, Clinical Trial Conduct Unit Brussels, Belgium, B-1000 France HÔPITAL SAINT-LOUIS, Service Hématologie Adultes Paris, France, 75010 Collapse <<
  NCT02678182	Adenocarcinoma of the Oesophag... more >>us Adenocarcinoma of the Gastro-oesophageal Junction Adenocarcinoma of the Stomach Collapse <<	Phase 2	Recruiting	August 2021	United Kingdom ... more >> The Royal Marsden NHS Foundation Trust, Downs Road, Sutton Recruiting Downs Road, Sutton, United Kingdom, SM2 5PT Contact: Bijal Patel       bijal.patel@rmh.nhs.uk    Contact: Claire Saffery       claire.saffery@rmh.nhs.uk Collapse <<
  NCT00457470	Diabetes Mellitus ... more >> Diabetic Retinopathy Collapse <<	Phase 2	Withdrawn(Cancelled before fir... more >>st patient enrolled) Collapse <<	-	-

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• 参考文献

• [1] 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.

  [2] 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.

  [3] Kondrashova O, Topp M, et al. Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nat Commun. 2018 Sep 28;9(1):3970.

  [4] Rucaparib