JNJ-7706621 - Aurora Kinase 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEJNJ-7706621Cat. No.: HY-10329CAS No.: 443797-96-4分式: CHFNOS分量: 394.36作靶點(diǎn): Aurora Kinase; CDK作通路: Cell Cycle/DNA Damage; Epigenetics儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 125 mg/mL

2、(316.97 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.5358 mL 12.6788 mL 25.3575 mL5 mM 0.5072 mL 2.5358 mL 5.0715 mL10 mM 0.2536 mL 1.2679 mL 2.5358 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。體內(nèi)實(shí)驗(yàn) 請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍福渲魄罢?qǐng)先配制澄清的儲(chǔ)備液，再依次添加助溶劑(為保證實(shí)

3、驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (5.27 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.08 mg/mL (5.27 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師ww

4、w.MedChemEBIOLOGICAL ACTIVITY物活性 JNJ-7706621種有效的 aurora kinase 抑制劑，同時(shí)能有效抑制 CDK1 和 CDK2，對(duì)CDK1，CDK2，Aurora-A 和 Aurora-B 的 IC50 值分別為 9，3，11 和 15 nM。IC50 & Target CDK2/cyclinE cdk2/cyclin A Cdk1/cyclin B CDK3/Cyclin E3 nM (IC50) 4 nM (IC50) 9 nM (IC50) 58 nM (IC50)CDK6/cyclinD1 Cdk4/cyclin D1 Aurora A A

5、urora B175 nM (IC50) 253 nM (IC50) 11 nM (IC50) 15 nM (IC50)VEGF-R1 VEGF-R2 VEGF-R3 FGF-R16400 nM (IC50) 154 nM (IC50) 735 nM (IC50) 575 nM (IC50)FGF-R2 GSK3226 nM (IC50) 254 nM (IC50)體外研究 JNJ-7706621 shows antiproliferative activity against various human tumor cells with IC50s of 284, 254, and447 n

6、M for HeLa, HCT116, and A375, respectively 1. JNJ-7706621 inhibits other centrosomal proteins suchas TOG, Nek2, and TACC3 in early mitotic phase, but does not prevent localization of Aurora A to the spindlepoles. Treatment of nocodazole-synchronized cells with JNJ-7706621 can override mitotic arrest

7、 bypreventing spindle checkpoint signaling, resulting in failure of chromosome alignment and segregation 2.JNJ-7706621 suspensions inhibits cell viability of HeLa cells with IC50s of 2.1 and 0.9 g/mL at 24 and 48 h.The IC50 of the JNJ-7706621-loaded nanoparticles are 35 and 2.7 g/mL and the IC50 of

8、the JNJ-7706621-loaded micelles are 6.3 and 1.6 g/mL 3. JNJ-7706621 shows inhibition of Aurora-A and Aurora-B but hasno activity at the highest concentration tested on the Plk1 or Wee1 serine/threonine kinases. JNJ-7706621also shows potent growth inhibition in vitro on all human cancer cell types wi

9、th IC50 values ranging from 112to 514 nM 4.體內(nèi)研究 JNJ-7706621 (100 mg/kg, i.p.) exhibits 95% tumor growth inhibition in A375 (human melanoma) tumorxenograft model 1. JNJ-7706621-loaded micelles inhibit tumor growth, and delay the tumor growth moreefficiently than the control JNJ-7706621 suspension 3.

10、JNJ-7706621 (100 and 125 mg/kg) is efficacious in ahuman tumor xenograft model under intermittent dosing regimens 4.PROTOCOLKinase Assay 4 To identify compounds that inhibit CDK1 kinase activity, a screening method is developed using theCDK1/cyclin B complex to phosphorylate a biotinylated peptide s

11、ubstrate containing the consensusphosphorylation site for histone H1, which is phosphorylatedin vivo by CDK1. Inhibition of CDK1 activity ismeasured by observing a reduced amount of 33P-g-ATP incorporation into the immobilized substrate instreptavidin-coated 96-well scintillating microplates. CDK1 e

12、nzyme is diluted in 50 mM Tris-HCl (pH 8), 10mM MgCl2, 0.1 mM Na3VO4, 1 mM DTT, 1% DMSO, 0.25 AM peptide, 0.1 ACi per well 33P-g-ATP (2,000-3,000 Ci/mmol), and 5 AM ATP in the presence or absence of various concentrations of test compound andincubated at 30C for 1 hour. The reaction is terminated by

13、 washing with PBS containing 100 mM EDTA and2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEplates are counted in a scintillation counter. Linear regression analysis of the percent inhibition by testcompound is used to determine IC50 values. The Aurora kinase assays are done with 10 AM ATP and apep

14、tide containing a dual repeat of the kemptide phosphorylation motif.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 3 HeLa cells are seeded in 96-well plates at the density of 2500 viable cells per well. The cells are thenincubated with a sus

15、pension of JNJ-7706621, JNJ-7706621-loaded micelles and nanoparticles (JNJ-7706621 concentrations of 0.011, 0.022, 0.11, 0.22, 1.1, 2.2, 11 and 22 g/mL; dilutions are made in themedium) and drug-free polymeric micelles (polymers concentrations 0.3 mg/mL) and nanoparticles (polymersconcentration 5 mg

16、/mL) for 4, 24 and 48 h. The cytotoxicity is assessed using the MTT test. Absorbance ismeasured at 570 nm using a microplate reader. Untreated cells are taken as control with 100% viability andTriton X-100 1% is used as positive control of cytotoxicity. The results are expressed as mean values stand

17、ard deviations of five measurements.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Briefly, animals are implanted s.c. with 1 mm3 A375 tumor fragments in the hindflank. After tumors reach 62Administration 4 to 126 mg, groups are pair matched. An

18、imals are given JNJ-7706621 or vehicle control starting on day 1.The tumor growth delay method is followed where each animal is euthanized when its neoplasm reached apredetermined size of 2.0 g. All statistical analyses are conducted using unpaired t tests at a P level of 0.05(two tailed).MCE has no

19、t independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Cell Chem Biol. 2019 Jun.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Huang S, et al. Synthesis and evaluation of N-acyl sulfonamides as potential prodrugs of cyclin-dependent kinase inhibitor JNJ-7706621. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3639-41. Epub 2006 May 6.2. Matsuhashi A, et al. Growth suppression and mitotic defect induced by JNJ-7706621, an inh