PHA-793887 - CDK 抑制剂 - 生命科学试剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPHA-793887Cat. No.: HY-11001CAS No.: 718630-59-2分式: CHNO分量: 361.48作靶点: CDK作通路: Cell Cycle/DNA Damage储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 50 mg/mL (138.32 mM)* means soluble, but

2、saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.7664 mL 13.8320 mL 27.6640 mL5 mM 0.5533 mL 2.7664 mL 5.5328 mL10 mM 0.2766 mL 1.3832 mL 2.7664 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备

3、液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.92 mM); Clear solutionBIOLOGICAL ACTIVITY1/3 Master of Small Molecules 您边的抑制剂师www.MedChemE物活性 PHA-793887种有效的，ATP 竞争性的 CDK 抑制剂，可抑制 Cdk2，Cdk1，Cdk4 和 Cdk9 的活性，IC50 值分别为 8 nM，60 nM，62 nM 和

4、 138 nM，同时可抑制糖原合酶激酶 3 (GSK-3)，IC50 值为 79 nM。IC50 & Target Cdk5/p25 cdk2/cyclin A CDK2/cyclinE CDK7/cyclin H5 nM (IC50) 8 nM (IC50) 8 nM (IC50) 10 nM (IC50)Cdk1/cyclin B Cdk4/cyclin D1 CDK9/cyclinT1 GSK-360 nM (IC50) 62 nM (IC50) 138 nM (IC50) 79 nM (IC50)体外研究 PHA-793887 partially inhibits Rb phospho

5、rylation at 1 M and almost completely at 3 M, in A2780 tumor cellline. PHA-793887 (1 M) partially inhibits phosphorylation of the Cdk2 substrates Rb and NPM in A2780 tumorcell line. PHA-793887 (6 M) significantly inhibits Rb and NPM phosphorylation in MCF7 cell line 1. PHA-793887 shows cytotoxic act

6、ivities against leukemic cell lines in vitro, with IC50 ranging from 0.3 to 7 M. Incolony assays, PHA-793887 is highly cytotoxic for leukemia cell lines, with an IC50 50 in the 5 to 140 nM range3.体内研究 PHA-793887 induces tumor growth inhibition in the range of 50% at dose of 15 mg/kg to 75% at dose o

7、f 30mg/kg in CD-1 nude mice. PHA-793887 (30 mg/kg, i.v.) also induces significant downregulation of the 58-genepanel in the skin of CD-1 mice 1. PHA-793887 (20 mg/kg, i.v.) induces tumor regression in the HL60 model. Inthe K562 model, PHA-793887 significantly reduces tumor growth. Moreover, PHA-7938

8、87 (20 mg/kg, i.v.)inhibits human primary leukemia growth in engraftment setting in vivo 3.PROTOCOLCell Assay 3 Cytotoxicity assays are performed using the Alamar blue vital dye. For each cell line, preliminarydoseresponse curves are performed to establish the cell-concentration range, giving a line

9、ar relationshipwith fluorescence. For cell lines, 5,000 to 20,000 cells are plated in 200 L complete medium in 96-wellplates, in the presence or absence of increasing doses of drugs (0.0110 M). For ALL-2 and AML-PSleukemias 10 105 cells/well are plated in StemSpanSFEM medium and treated with the sam

10、e range of drugconcentrations. Peripheral blood mononuclear cells and cord blood CD34+ cells are plated 1 105 cells/wellin presence or absence of 1 g/mL phytohemagglutin or growth factor cocktail (50 ng/mL stem cell factor, 20ng/mL each of granulocyte-macrophage colony-stimulating factor, granulocyt

11、e colony-stimulating factor,interleukin-3, interleukin-6, and 3 U/mL erythropoietin), respectively. In all cases, after 48 hours culture, 1/10volume Alamar blue solution is added and incubated overnight. The plates are then read in a fluorimeter withexcitation at 535 nm and emission at 590 nm. Cytot

12、oxicity is calculated as percentage of fluorescence withrespect to untreated control, after subtracting for background fluorescence in absence of cells.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal 107 HL60 and K562 cells are inoculated subcuta

13、neously in SCID mice. Animals are randomized in sevenAdministration 3 mice per group. PHA-793887 is administered at 20 mg/kg intravenous (IV) once a day, continuously for 10days (from day 9 to day 18) in HL60 model and with a two 5-day cycles (from day 9 to day 13 and from day17 to day 21) in K562-b

14、earing mice. Glivec is orally administered for 9 consecutive days from day 9 onwardin the K562 xenograft model. Tumor growth and net body weight are evaluated twice a week. The tumor2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEweight is calculated according to the following formula: tumor weight

15、 = length (mm) width2 (mm) /2. Theeffect of the anticancer treatment is determined as the delay in onset of an exponential growth of tumors.This delay (T C value) is defined as the difference of median time (in days) required for the tumors oftreatment (T) and control groups (C) to reach a predeterm

16、ined size. Toxicity is evaluated on the basis of thebody weight reduction.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Harvard Medical School LINCS LIBRARYSee more customer validations o

17、n HYPERLINK / www.MedChemEREFERENCES1. Locatelli G, et al. Transcriptional analysis of an E2F gene signature as a biomarker of activity of the cyclin-dependent kinase inhibitorPHA-793887 in tumor and skin biopsies from a phase I clinical study. Mol Cancer Ther. 2010 May;9(5):1265-73.2. Massard C, et

18、 al. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2,1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011 Mar 15;10(6):963-70. Epub 2011 Mar 15.3. Alzani R, et al. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemiamodels. Exp Hematol. 2010 Apr;38(4):259-269.e2.4. Brasca MG, et al. Optimization of 6,6-dimethyl pyrrolo3,4-cpyrazoles: Identification of PHA-793887, a potent CDK