生物活性

• 靶点

  PARP1 IC50:5nM

  PARP2 IC50:1nM

• 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 it possesses various cellular function, including regulation of apoptosis and chromosome stability, gene amplification and transcription, as well as cell division and differentiation. PARP-2 is the closest homolog of PARP1 (~62% similarity in catalytic domain) and compensates for PARP-1 activity in DNA single-strand break repair^[1]. Olaparib, also called as AZD2281 or Ku-0059436, one of the best investigated third-generation PARP inhibitors^[2], can potently inhibit both PARP-1 (IC50=5nM) and PARP-2(IC50=1nM)^[1]. BRCA1-deficient cell lines, such as MDA-MB-436 and HCC1937, were hypersensitive to olaparib than BRCA1- and BRCA2-proficient cell lines (Hs578T, MDA-MB-231 and T47D). Also olaparib shows good pharmacokinetic profiles, oral bioavailability, as well as activity in vivo^[1]. These facilitate olaparib approved for use in recurrent ovarian cancer and germline BRCA HER2-negative metastatic breast cancer^[2].
• 作用机制Olaparib occupies the NAD binding pocket at the catalytic site, which has been proposed to trap PARP1 on DNA.^[3]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  5637	-	Growth Inhibition Assay	-	IC50=7.9286 μM	SANGER
  697	-	Growth Inhibition Assay	-	IC50=2.84173 μM	SANGER
  769-P	-	Growth Inhibition Assay	-	IC50=24.8466 μM	SANGER

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• 动物研究
  剂量	Mice: min = 10 mg/kg[4], max = 200 mg/kg[5]
  给药途径	p.o., i.v., i.p.

• 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
  NCT02571725	Ovarian Cancer ... more >> Fallopian Tube Cancer Peritoneal Neoplasms Collapse <<	Phase 1 Phase 2	Recruiting	February 2022	United States, Florida ... more >> Moffitt Cancer Center Recruiting Tampa, Florida, United States, 33612 Contact: Eleni Rokakis, BSN, RN    813-745-3593    Eleni.Rokakis@moffitt.org    United States, New Mexico Southwest Gynecologic Oncology Associates Recruiting Albuquerque, New Mexico, United States, 87106 Contact: Karen Finkelstein, MD    505-843-7813       University of New Mexico Comprehensive Cancer Center Recruiting Albuquerque, New Mexico, United States, 87131 Contact: Valerie Parks, RN    505-925-0390    vparks@salud.unm.edu    Principal Investigator: Sarah F Adams, MD          United States, Ohio The Ohio State University Recruiting Columbus, Ohio, United States, 43210 Contact: David M O'Malley, MD    614-685-6411       Contact: Molly Myers    614-685-6411    molly.myers@osumc.edu    United States, Virginia University of Virginia Cancer Center Recruiting Charlottesville, Virginia, United States, 22903 Contact: Anne Gabel    434-982-6657    am7bd@virginia.edu Collapse <<
  NCT03579784	Advanced Gastric Cancer	Phase 2	Recruiting	April 30, 2020	Korea, Republic of ... more >> Seoul National University Hospital Recruiting Seoul, Korea, Republic of, 110-744 Contact: Do-Youn Oh, MD, PhD    82-2-2072-0701    ohdoyoun@snu.ac.kr Collapse <<
  NCT01972217	Metastatic Castration-resistan... more >>t Prostate Cancer Collapse <<	Phase 2	Active, not recruiting	December 31, 2018	-

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• 参考文献

• [1] Menear KA, Adcock C, et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl] -2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91.

  [2] Chen Y, Zhang L, et al. Olaparib: a promising PARP inhibitor in ovarian cancer therapy. Arch Gynecol Obstet. 2013 Aug;288(2):367-74.

  [3] Murai J, Huang SY, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99.