生物活性

• 靶点

  CDK5 IC50:0.16μM

  CDK2 IC50:0.7μM

  CDK1 IC50:0.65μM

• 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. Roscovitine (Seliciclib, CYC202) is a CDK2 and CDK5 inhibitor with IC50 values of 0.65, 0.7, 0.7 and 0.16 μM for cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk5/p35 (measured by purified kinases activity), respectively. Roscovitine had a very limited effect on the cdk4/cyclin D1 and cdk6/cyclin D2 kinases (IC50 values >100 μM)^[1]. It also exhibited the potency to CDK7/cyclin H with IC50 value of 0.49 μM. Roscovitine showed anti-growth effect against a panel of human tumor cell lines in cell culture, including A549, CHAGO-K1, NCI-H69, NCI-H460, LOVO, HCT15, HCT116, HT29, A498, ACHN, HT1376, MCF7, MDAMB435S, AN3CA, MES-SA, MES-SA/Dx5 and HepG2 cell lines, with IC50 values ranging from 7.9 - 30.2 μM for 72h^[2]. Treatment of 60 μM roscovitine for 48h could inhibit the growth of L1210 cells and arrest cells in G2M^[1]. Lovo xenografted mice treated with roscovitine, 100 mg/kg intraperitoneally 3 times daily at 8 hourly intervals for 5 days, exhibited a statistically significant reduction of 44.8% in tumor growth^[2]. Phase 2 studies of roscovitine treatment for cystic fibrosis and Cushing's Disease, and phase 1 study of roscovitine combined with sapacitabine treatment for advanced solid tumors are recruiting now (see https://www.clinicaltrials.gov/).
• 作用机制Roscovitine behaves as a competitive inhibitor for ATP binding to cdc2.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  697	-	Growth Inhibition Assay	-	IC50=12.6007 μM	SANGER
  A101D	-	Growth Inhibition Assay	-	IC50=18.3208 μM	SANGER
  A3-KAW	-	Growth Inhibition Assay	-	IC50=5.76116 μM	SANGER

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• 动物研究
  剂量	Mice[4] (i.p.): min = 50 mg/kg, max = 350 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Rats[5] Dose 25 mg/kg Administration i.p. Cmax 15.8 ± 0.4 μg/ml Vss 102 ± 13 ml CL 11.3 ± 1.2 ml/h Tβ 7.2 ± 1.4 h (elimination half-life) AUC 66.8 ± 7.2 h·μg/g Tα 0.59 ± 0.14 h (absorption half-life)

• 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
  NCT00372073	Non-small Cell Lung Cancer	Phase 2	Terminated	March 2012	United States, Arizona ... more >> Arizona Cancer Center Tucson, Arizona, United States, 85724 United States, California Pacific Coast Hematology Oncology Group Fountain Valley, California, United States, 92708 United States, Florida Pasco Hernando Oncology New Port Richey, Florida, United States, 34652 United States, Illinois Rush University Medical Center Chicago, Illinois, United States, 60612 The University of Chicago Chicago, Illinois, United States, 60637 United States, Maryland University of Maryland, Greenebaun Cancer Center Baltimore, Maryland, United States, 21201 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02115 United States, Nebraska Nebraska Medical Center Omaha, Nebraska, United States, 68198 United States, Nevada Nevada Cancer Research Foundation Las Vegas, Nevada, United States, 89106 VA Sierra Nevada Health Care System Reno, Nevada, United States, 89502 United States, New Mexico New Mexico Oncology Hematology Consultants Albuquerque, New Mexico, United States, 87109 United States, New York Columbia Presbyterian Medical Center New York, New York, United States, 10032 United States, Pennsylvania Penn State Milton S. Hershey Medical Center Hershey, Pennsylvania, United States, 17033 University of Pittsburg Cancer Institute Pittsburgh, Pennsylvania, United States, 15232 United States, Tennessee The Family Cancer Center Collierville, Tennessee, United States, 38017 Vanderbilt University Medical Center Nashville, Tennessee, United States, 37232 United States, Texas Southwest Regional Cancer Center Austin, Texas, United States, 78705 Center for Oncology Research and Treatment Dallas, Texas, United States, 75230 East Texas Medical Center Tyler, Texas, United States, 75701 United States, Virginia Danville Hematology Oncology Danville, Virginia, United States, 24541 Collapse <<
  NCT00999401	Advanced Solid Tumors	Phase 1	Unknown	July 2018	United States, Massachusetts ... more >> Dana Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02115 Contact: Geoffrey Shapiro, M.D.    617-632-4942       Contact: Tracy Bell, R.N.    617.632.3482       Dana Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 Contact: Sara Tolaney, M.D.    617-632-2335       Contact: Leilani Anderson, RN    617-632-3129 Collapse <<
  NCT01333423	Breast Cancer	Phase 1	Withdrawn	-	-

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• 参考文献

• [1] Meijer L, Borgne A, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997 Jan 15;243(1-2):527-36.

  [2] McClue SJ, Blake D, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer. 2002 Dec 10;102(5):463-8.

  [3] De Azevedo WF, Leclerc S, et al. Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem. 1997 Jan 15;243(1-2):518-26.

  [4] Song H, Vita M, et al. Effect of the Cdk-inhibitor roscovitine on mouse hematopoietic progenitors in vivo and in vitro. Cancer Chemother Pharmacol. 2007 Nov;60(6):841-9. Epub 2007 Feb 22.

  [5] Sallam H, Jimenez P, et al. Age-dependent pharmacokinetics and effect of roscovitine on Cdk5 and Erk1/2 in the rat brain. Pharmacol Res. 2008 Jul;58(1):32-7.

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