JNJ-7706621 化学構造
分子量: 394.36

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製品説明

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製品の説明

生物活性

製品説明 JNJ-7706621は新型有効の広い譜CDKとAuroraキナーゼ阻害剤、IC50が3-253nMになる。
ターゲット CDK1/Cyclin B CDK2/Cyclin A CDK2/Cyclin E Aurora-A Aurora-B
IC50 9 nM 4 nM 3 nM 11 nM 15 nM [1]
In vitro試験 JNJ-7706621 also shows some inhibition to VEGF-R2, FGF-R2, and GSK3β, with IC50 of 154-254 nM. JNJ-7706621 shows inhibitory effect on a panel of human cancer cell types, including HeLa, HCT-116, SK-OV-3, PC3, DU145, A375, MDA-MB-231, MES-SA, and MES-SA/Dx5, with IC50 of 112-514 nM, independent of p53, retinoblastoma, or P-glycoprotein status. JNJ-7706621 is several-fold less potent at inhibiting growth of normal cell types, including MRC-5, HASMC, HUVEC, and HMVEC, with IC50 of 3.67-5.42 μM. In HeLa or U937 cells, JNJ-7706621 (0.5-3 μM) delays exit from G1, arrests cells in G2-M, induces endoreduplication, activates apoptosis, and reduces colony formation. [1] In a HeLa cell line, incremental treatment with increasing concentrations of JNJ-7706621 leads to a 16-fold resistance, which may be mediated by ABCG2. [2]
In vivo試験 In mouse xenograft model of A375 melanoma human tumor, JNJ-7706621 (100 or 125 mg/kg) causes tumor regression. [3]
臨床試験
特集 A broad-spectrum inhibitor.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

In vitro kinase assay for CDK1 and Aurora kinases For CDK1 kinase activity, a method is developed using the CDK1/cyclin B complex purified from baculovirus to phosphorylate a biotinylated peptide substrate containing the consensus phosphorylation site for histone H1, which is phosphorylated in vivo by CDK1. Inhibition of CDK1 activity is measured by observing a reduced amount of 33P-γ-ATP incorporation into the immobilized substrate in streptavidin-coated 96-well scintillating microplates. CDK1 enzyme is diluted in 50 mM Tris-HCl (pH 8), 10 mM MgCl2, 0.1 mM Na3VO 4, 1 mM DTT, 1% DMSO, 0.25 μM peptide, 0.1 μCi per well 33P-γ-ATP, and 5 μM ATP in the presence or absence of various concentrations of JNJ-7706621 and incubated at 30 °C for 1 hour. The reaction is terminated by washing with PBS containing 100 mM EDTA and plates are counted in a scintillation counter. Linear regression analysis of the percent inhibition by JNJ-7706621 is used to determine IC50. The Aurora kinase assays are done with 10 μM ATP and a peptide containing a dual repeat of the kemptide phosphorylation motif.

細胞アッセイ: [3]

細胞株 HeLa, HCT-116, A375, SK-OV-3, MDA-MB-231, and PC-3 cells
濃度 1 nM - 10 μM, dissolved in DMSO
反応時間 48 hours
実験の流れ The ability of JNJ-7706621 to inhibit the proliferation of cell growth is determined by measuring incorporation of 14C-labelled thymidine into newly synthesized DNA within the cells. Cells are trypsinized and counted and 3-8 × 103 cells are added to each well of a 96-well CytoStar tissue culture treated scintillating microplate in complete medium in a volume of 100 μL. Cells are incubated for 24 hours in complete medium at 37 °C in an atmosphere containing 5% CO2. Next, 1 μL of JNJ-7706621 is added to the wells of the plate. Cells are incubated for 24 more hours. Methyl 14C-thymidine 56 mCi/mmol is diluted in complete medium and 0.2 μCi/well is added to each well of the CytoStar plate in a volume of 20 μL. The plate is incubated for 24 hours at 37 °C in JNJ-7706621 plus 14C-thymidine. The contents of the plate are discarded and the plate is washed twice with 200 μL PBS. 200 μL of PBS is added to each well. The top of the plate is sealed with a transparent plate sealer and a white plate backing sealer is applied to the bottom of the plate. The degree of methyl 14C-thymidine incorporation is quantified on a Packard Top Count.

動物実験: [1]

動物モデル Mouse xenograft model of A375 cells
製剤 Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
投薬量 100 or 125 mg/kg
投与方法 Orally or by intraperitoneal injection injection

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download JNJ-7706621 SDF
分子量 394.36
化学式

C15H12F2N6O3S

CAS No. 443797-96-4
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 79 mg/mL (200.32 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose+0.2% Tween 80 14 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名  4-​[[5-​amino-​1-​(2,​6-​difluorobenzoyl)​-​1H-​1,​2,​4-​triazol-​3-​yl]​amino]​-benzenesulfonamide

文献中の引用 (8)

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