生物活性

• 描述Cyclin dependent kinases (CDKs) are a family of serine/threonine kinases that, in concert with cyclins (positive regulators) and natural inhibitors (CDKI), control the cell cycle progression. PHA -793887 is a novel and effective CDK2, CDK5 and CDK7 inhibitor with IC₅₀ of 8 nM, 5 nM and 10 nM, respectively. A2780 ovarian carcinoma cells were treated with PHA-793887 for 24 h at the concentration of 3 μM and 1 μM. A decrease in the S phase population and a subsequent increase of the G1 population, as expected for inhibition of CDK2/cyclin A, were observed at 1 μM treatment compared to the control cells. At 3 μM only a strong G2/M increase was observed, which can be ascribed to inhibition of CDK1/cyclin B. The presence of cells with sub G1 DNA content (from 2.6% in control cells to 26.2% in cells treated with PHA-793887 at 3 μM) clearly implied cell death and apoptosis. A clear reduction in DNA synthesis was observed, compared to the control group. A clear reduction of the hyperphosphorylated form of pRb (retinoblastoma protein, a known CDK substrate) and an accumulation of the hypophosphorylated form of pRb were observed in the extracts of treated cell. PHA-793887 (1 or 3 μM) decreases the amount of pRB (retinoblastoma protein, a known CDK substrate) phosphorylation in treated cells in comparison with untreated cells. PHA-793887 caused a dose-dependent inhibition of the A2780 tumor growth up to 76% at the dose of 30 mg/kg in the human ovarian A2780 xenograft mouse model^[4].
• 作用机制The pyrrolo-pyrazole system of PHA-793887 occupies the adenine region of the ATP pocket, while the iso-butyl group points towards the solvent accessible region.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A2780 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A2780 cells after 72 hrs by fluorescence assay, IC50=0.09 μM	20153204
  human A2780 cells	3 μM	Function assay	-	Inhibition of CDK in human A2780 cells assessed as accumulation of hypophosphorylated form of retinoblastoma protein at 3 uM by immunohistochemistry	20153204
  human A375 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A375 cells after 72 hrs by SRB assay, IC50=0.396 μM	20153204

• 更多

• 动物研究
  剂量	CD-1 nude mice: 15 mg/kg, 30 mg/kg[3] (i.v.)
  给药途径	i.v.
  动物药代数据	Animal Nude mice[1] Dose 10 mg/kg Administration i.v. T1/2 4.1 h AUC 19.2 μM·h CL 23.9 ml/min/kg Cmax 36.5 μM Vss 1360 ml/kg

• 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
  NCT00996255	Advanced/Metastatic Solid Tumo... more >>rs Collapse <<	Phase 1	Terminated	-	France ... more >> Institut Gustave-Roussy Villejuif Cedex, France, 94805 United Kingdom St. James University Hospital Leeds, United Kingdom, LS9 7TF Collapse <<

• 参考文献

• [1] Brasca MG, Albanese C, et al. Optimization of 6,6-dimethyl pyrrolo[3,4-c] pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorg Med Chem. 2010 Mar 1;18(5):1844-53.

  [2] Alzani R, Pedrini O, et al. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Exp Hematol. 2010 Apr;38(4):259-269.e2.

  [3] Locatelli G, Bosotti R, et al. Transcriptional analysis of an E2F gene signature as a biomarker of activity of the cyclin-dependent kinase inhibitor PHA-793887 in tumor and skin biopsies from a phase I clinical study. Mol Cancer Ther. 2010 May;9(5):1265-73.

  [4] Brasca MG, Albanese C, Alzani R, Amici R, Avanzi N, Ballinari D, Bischoff J, Borghi D, Casale E, Croci V, Fiorentini F, Isacchi A, Mercurio C, Nesi M, Orsini P, Pastori W, Pesenti E, Pevarello P, Roussel P, Varasi M, Volpi D, Vulpetti A, Ciomei M. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. doi: 10.1016/j.bmc.2010.01.042. Epub 2010 Jan 25. PMID: 20153204.