2-(4-{6-chloro-2-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridin-7-yl}piperazin-1-yl)-N-(1,3-thiazol-2-yl)acetamide

• ChemBase编号: 72720
• 分子式: C23H25ClN8OS
• 平均质量: 497.0156
• 单一同位素质量: 496.15605614
• SMILES: c1(cnc2c(c1N1CCN(CC1)CC(=O)Nc1sccn1)nc([nH]2)c1ccc(cc1)N(C)C)Cl
• Canonical SMILES: O=C(Nc1nccs1)CN1CCN(CC1)c1c(Cl)cnc2c1nc([nH]2)c1ccc(cc1)N(C)C
• InChI: InChI=1S/C23H25ClN8OS/c1-30(2)16-5-3-15(4-6-16)21-28-19-20(17(24)13-26-22(19)29-21)32-10-8-31(9-11-32)14-18(33)27-23-25-7-12-34-23/h3-7,12-13H,8-11,14H2,1-2H3,(H,25,27,33)(H,26,28,29)
• InChIKey: QYKHWEFPFAGNEV-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 2-(4-{6-chloro-2-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridin-7-yl}piperazin-1-yl)-N-(1,3-thiazol-2-yl)acetamide
• IUPAC传统名: 2-(4-{6-chloro-2-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridin-7-yl}piperazin-1-yl)-N-(1,3-thiazol-2-yl)acetamide
• 别名: CCT129202

登记号

• CAS号: 942947-93-5
• PubChem SID: 162037641
• PubChem CID: 16202152

理论计算性质

• Acid pKa: 10.173994
• 质子受体: 7
• 质子供体: 2
• LogD (pH = 5.5): 3.1510677
• LogD (pH = 7.4): 3.3521101
• Log P: 3.356644
• 摩尔折射率: 146.6215 cm^3
• 极化性: 51.627865 Å^3
• 极化表面积: 93.28 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: true

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Aurora kinase

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1519

Research Area

• Description: Cancer

Biological Activity

• Description: CCT129202 is an ATP-competitive pan-Aurora inhibitor for Aurora A, Aurora B and Aurora C with IC50 of 0.042 μM, 0.198 μM and 0.227 μM, respectively.
• Targets: Aurora A; Aurora B; Aurora C
• IC50: 0.042 μM; 0.198 μM; 0.227 μM ^[1]
• In Vitro: CCT129202 is an ATP-competitive inhibitor of recombinant Aurora A kinase with a Ki of 49.8 nM. CCT129202 at 1 μM shows high selectivity for Aurora A and Aurora B with 92% and 60% inhibition, respectively. It inhibits FGFR3 slightly by 27%, and is not active against CRAF. CCT129202 inhibits proliferation in multiple cultures of human tumor cell lines with half-maximal growth inhibition (GI50) values ranging from 0.08 μM for MV4-11 to 1.7 μM for MDA-MB-157. The effects are in association with increased expression levels of Aurora A and Aurora B leading to aberrant mitosis. Treatment with CCT129202 (0.7 μM) causes the accumulation of HCT116 cells with ≥4N DNA content, leading to apoptosis in a time dependent manner. Application of CCT129202 in HCT116 cells causes decreased histone H3 phosphorylation and increased p53 protein stabilization, which are consistent with the inhibition of Aurora B and Aurora A, respectively. CCT129202 induces up-regulation of p21 in HCT116, HT29 and Hela cells in a p53 dependent and independent manner, which leads to decreased phosphorylation of the Rb protein and activity of E2F in a concentration-dependent manner. ^[1]
• In Vivo: Administration of CCT129202 at 100 mg/kg in athymic mice bearing s.c. HCT116 colon cancer xenografts causes ~50% reduction of histone H3 phosphorylation after 30 minutes of treatment, and significantly inhibits tumor growth by 57.7% compared to control mice after a period of 9 days of treatment. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• Inhibition of Aurora Kinases: NH2-terminal glutathione S-transferase (GST)-fusion recombinant human Aurora A (aa 118-403), Aurora B (full length), and Aurora C (full length) are expressed in baculovirus, purified, and used in the kinase inhibition assays. The in vitro kinase assays are performed in kinase buffer (50 mM Tris pH 7.5, 10 mM NaCl, 2.5 mM MgCl₂ and 1 mM DTT) containing γ-^32P-ATP, Aurora kinase and different concentrations of CCT129202. The reactions are incubated for 30 minutes at 30 °C and stopped by adding sample buffer. The reactions are separated on Novex Tris-Glycine gels and dried on a vacuum gel drier at 80 °C for 1 hour before exposure to Kodak-Biomax XR film. The concentration of CCT129202 that inhibits Aurora kinases by 50% is calculated representing IC50 value.
• Protocol: Cell Assay ^[1]
• Cell Lines: Colo205, SW620, HCT116, HT29, KW12, Hela, A2780, OVCAR8, MDA-MB-157 and MV4-11 cell lines
• Concentrations: Dissolved in DMSO, final concentration ~50 μM
• Incubation Time: 72 hours
• Methods: Cells are treated with a range of 0 to 50 uM of CCT129202 for 72 hours. Cell proliferation is analyzed with the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The absorbance is measured at 570 nm using the Wallac VICTOR2TM 1420 Multilabel Counter.
• Protocol: Animal Study ^[1]
• Animal Models: HCT116 colon carcinoma is established in female NCr athymic mice.
• Formulation: Dissolved in 10% DMSO, 5% Tween 20 in saline
• Doses: ~100 mg/kg
• Administration: Injection i.p

References

• References: [1] Chan F, et al. Mol Cancer Ther. 2007, 6(12), 3147-3157.

参考文献

• Chan F, et al. Mol Cancer Ther. 2007, 6(12), 3147-3157.