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PHA-793887

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Chemical Structure| 718630-59-2 同义名 : -
CAS号 : 718630-59-2
货号 : A184364
分子式 : C19H31N5O2
纯度 : 99%+
分子量 : 361.482
MDL号 : MFCD17169992
存储条件：

粉末 Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(138.32 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 10 mg/mL clear

PO 0.5% CMC-Na 30 mg/mL suspension

生物活性
靶点

  • CDK5

    CDK5/p25, IC50:5 nM

  • CDK4

    CDK4/CyclinD1, IC50:62 nM

  • CDK2

    CDK2/CyclinE, IC50:8 nM

    CDK2/CyclinA, IC50:8 nM

  • CDK9

    CDK9/CyclinT1, IC50:138 nM
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
细胞系 浓度 检测类型 检测时间 活动说明 数据源
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
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.77mL

0.55mL

0.28mL

13.83mL

2.77mL

1.38mL

27.66mL

5.53mL

2.77mL
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.