生物活性

• 靶点

  CDK1 IC50:10nM-210nM

  CDK2 IC50:10nM-210nM

  CDK4 IC50:10nM-210nM

  Cdk6 IC50:10nM-210nM

  Cdk9 IC50:10nM-210nM

• 描述The CDKs (cyclin dependent kinases), as direct regulators of specific phases of the cell cycle, can control cellular proliferation and transcription with their activating cyclin partners and subunit inhibitors. Thus, the inhibition of CDKs can be assessed with monitoring the phosphorylation state of specific substrates. For example, decreased phosphorylation of the CDK1 substrate PP1 a (T320) and the CDK2 substrates Rb (T821) and NPM (T199) can indicated the inhibition of the CDKs. Decreased phosphorylation of pSer5 and pSer2 of RNA pol II CTD would indicate inhibition of CDKs 7 and 9, respectively. AT7519 is a pan-CDKs inhibitor with IC50 values of 47, 13, <10 nM for CDK2/CyclinA, CDK5/p35 and CDK9/CyclinT, and modest activity against CDK1/CyclinB, CDK3/CyclinE, CDK4/CyclinD1 and CDK6/CyclinD3 with IC50 values of 210, 360, 100 and 170 nM, respectively (measured by in vitro kinase assays)^[1]. Treatment with 0.05-1uM AT7519 for 24h was sufficient to inhibit phosphorylation of the CDK1 substrate PP1a (T320) and the CDK2 substrates Rb (T821) and NPM (T199) in HCT116 cells^[2]. AT7519 on concentration of 0.5 μM induced rapid dephosphorylation at both RNA pol II CTD at both the serine 2 and serine 5 sites^[1]. AT7519 showed antiproliferative activity and apoptosis-induction in a panel of human tumor cell lines, including ovarian carcinoma, lung carcinoma, breast carcinoma, uterine sarcoma, leukemia and lymphoma, with IC50 values ranging from 40 to 940nM. AT7519 with concentration of 250-1000nM can induce G0-G1 and G2-M cell cycle blockade in HCT116 cells. Intraperitoneal or intravenous administration of 9.1mg/kg AT7519 twice a day for 9 consecutive days achieved completely tumor regression on day 15 in HCT116 tumor xenografts^[2]. Phase 2 studies of AT7519 treatment for mantle cell lymphoma and chronic lymphocytic leukemia have been completed (see in https://www.clinicaltrials.gov/).
• 作用机制The inhibition of CDK1 by AT7519 is competitive with ATP.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A2780 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.35 μM	18656911
  HCT116 cells	-	Cytotoxic assay	72 h	Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by Alamar blue assay, IC50=0.08 μM	26115571
  MRC5 cells	-	Proliferation assay	72 h	Antiproliferative activity against human MRC5 cells assessed as cell viability after 72 hrs by alamar blue assay, IC50=0.98 μM	18656911

• 动物研究
  剂量	Mice(i.p.): min = 5 mg/kg[2], max = 15 mg/kg[1]
  给药途径	i.p.
  动物药代数据	Animal Nude mice[3] Dose 5 mg/kg Administration i.v. / i.p. Cmax 1750 ng/ml (i.v.) 1886 ng/ml (i.p.) T1/2 1.1 h (i.v.) 1.6 h (i.p.) AUC0→∞ 1513 h·ng/ml (i.v.) 1628 h·ng/ml (i.p.) F 100% (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
  NCT01627054	Chronic Lymphocytic Leukemia	Phase 2	Completed	-	Canada, Manitoba ... more >> CancerCare Manitoba Winnipeg, Manitoba, Canada, R3E 0V9 Canada, Ontario Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT00390117	Lymphoma Unsp... more >>ecified Adult Solid Tumor, Protocol Specific Collapse <<	Phase 1	Completed	-	Canada, Ontario ... more >> Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT01183949	Multiple Myeloma	Phase 1 Phase 2	Completed	-	United States, Massachusetts ... more >> Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215 Massachusetts General Hospital Boston, Massachusetts, United States, MA02115 Dana Faber Cancer Institute Boston, Massachusetts, United States United States, New York Memorial Sloan-Kettering Cancer Centre New York, New York, United States, 10065 United States, Wisconsin MCW and Froedtert Clinical Cancer Center, Division of Neoplastic Diseases & Related Disorders Milwaukee, Wisconsin, United States, 53226 Collapse <<

• 更多
• 参考文献

• [1] Santo L, Vallet S, et al. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010 Apr 22;29(16):2325-36.

  [2] Squires MS, Feltell RE, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32.

  [3] Dolman ME, Poon E, et al. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clin Cancer Res. 2015 Nov 15;21(22):5100-9.