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PHA-680632

产品号 S1454 公司名称 Selleck Chemicals
CAS号 398493-79-3 公司网站 http://www.selleckchem.com
分子式 C28H35N7O2 电 话 (877) 796-6397
分子量 501.6232 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72687

产品价格信息

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产品别名

标题
PHA-680632
IUPAC标准名
N-(2,6-diethylphenyl)-3-[4-(4-methylpiperazin-1-yl)benzamido]-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxamide
IUPAC传统名
N-(2,6-diethylphenyl)-3-[4-(4-methylpiperazin-1-yl)benzamido]-1H,4H,6H-pyrrolo[3,4-c]pyrazole-5-carboxamide

产品登记号

CAS号 398493-79-3

产品性质

作用靶点 Aurora Kinase
成盐信息 Free Base
溶解度 DMSO
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, repectively.
Targets Aurora A Aurora B Aurora C
IC50 27 nM 135 nM 120 nM [1]
In Vitro PHA-680632 potently inhibits all three Aurora kinases (A, B, and C) with IC50 values of 27, 135, and 120 nM, respectively. PHA-680632 is selective for Aurora kinases, with 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, VEGFR2, and VEGFR3, and with IC50 higher than 10 μM for another 22 kinases. PHA-680632 shows potent anti-proliferative effects in a wide range of cell types with IC50 values of 0.06–7.15 μM, including HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells. PHA-680632 (0.5 μM) causes polyploidy in tumor cells. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. [1]PHA680632 in association with radiation leads to additive effects in cancer cells, especially in the p53-deficient cells. Combined ionising radiation (IR) and treatment of PHA680632 (100–400 nM) prior to IR leads to an enhancement of radiation-induced Annexin V positive cells, micronuclei formation, and Brca1 foci formation only in HCT116 cells with deficient p53, other than the p53 wild-type counterparts. [2]
In Vivo HA-680632 (15–60 mg/kg) inhibits tumor growth in mice xenografts models of HL60, A2780, and HCT116 cells, by reducing tumor cell proliferation and increasing apoptosis. PHA-680632 (45 mg/kg) suppresses growth of activated ras-driven mammary tumors in mouse mammary tumor virus v-Ha-ras transgenic mice and results in complete tumor stabilization and partial regression. [1]
Clinical Trials
Features
Protocol
Kinase Assay [1]
Aurora Kinase Inhibition Assay Inhibition of kinase activity by PHA-680632 is assessed using a scintillation proximity assay format. The biotinylated substrate is transphosphorylated by the kinase in presence of ATP traced with γ33-ATP. The phosphorylated substrate is then captured using streptavidin-coated scintillation proximity assay beads and the extent of phosphorylation is evaluated by β-counter after a 4-hour rest for the floatation of the beads on a dense 5 M CsCl solution. In particular, a peptide derived from the Chocktide sequence (LRRWSLGL) is used as substrate for Aurora A, whereas the optimized peptide Auroratide is employed for Aurora B and C. The assay is run in a robotized format on 96-well plates. The potency of the compound toward Aurora kinases is evaluated and IC50 values are determined.
Cell Assay [1]
Cell Lines HeLa, HCT116, HT29, LOVO, DU145, and NHDF cells
Concentrations 0.001-1 μM, dissolved in DMSO as 10 mM stock solution
Incubation Time 72 hours
Methods Cells (5×103 to 1.5×104 per cm2) are seeded in 24-well plate. After 24 hours, plates are treated with PHA-680632 and incubated for 72 hours. At the end of incubation time, cells are detached from each plate and counted using a cell counter. IC50s are calculated using percentage of growth versus untreated control.
Animal Study [2]
Animal Models Mice (female athymic nude) xenografts models of p53?/? HCT116 cells
Formulation Dissolved in 20% Tween-80 in 5% glucose solution
Doses 40 mg/kg
Administration Intraperitoneal (i.p.) injection twice a day
References
[1] Soncini C, et al. Clin Cancer Res, 2006, 12(13), 4080-4089.
[2] Tao Y, et al. Br J Cancer, 2007, 97(12), 1664-1672.