N-(4-{[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxy}phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine

• ChemBase编号: 73186
• 分子式: C28H21N7OS
• 平均质量: 503.57764
• 单一同位素质量: 503.15282933
• SMILES: c1cc(c(nc1)Oc1ccc(cc1)Nc1c2c(c(nn1)c1scc(c1)C)cccc2)c1nc(ncc1)N
• Canonical SMILES: Cc1csc(c1)c1nnc(c2c1cccc2)Nc1ccc(cc1)Oc1ncccc1c1ccnc(n1)N
• InChI: InChI=1S/C28H21N7OS/c1-17-15-24(37-16-17)25-20-5-2-3-6-21(20)26(35-34-25)32-18-8-10-19(11-9-18)36-27-22(7-4-13-30-27)23-12-14-31-28(29)33-23/h2-16H,1H3,(H,32,35)(H2,29,31,33)
• InChIKey: IVUGFMLRJOCGAS-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(4-{[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxy}phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine
• IUPAC传统名: N-(4-{[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxy}phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine
• 别名: AMG 900

登记号

• CAS号: 945595-80-2
• PubChem SID: 162038106
• PubChem CID: 24856041

理论计算性质

• Acid pKa: 15.16866
• 质子受体: 7
• 质子供体: 2
• LogD (pH = 5.5): 5.956634
• LogD (pH = 7.4): 5.9597664
• Log P: 5.9598064
• 摩尔折射率: 146.1819 cm^3
• 极化性: 57.956623 Å^3
• 极化表面积: 111.73 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: false

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Aurora

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2719

Research Area

• Description: Cancer

Biological Activity

• Description: AMG 900 is a potent and highly selective pan-Aurora inhibitor for Aurora A, Aurora B and Aurora C with IC50 of 5 nM, 4 nM and 1 nM, respectively.
• Targets: Aurora A; Aurora B; Aurora C; p38α
• IC50: 5 nM; 4 nM; 1 nM; 53 nM ^[1]
• In Vitro: AMG 900 is a novel class of ATP-competitive phthalazinamine small molecule inhibitors of aurora kinases. In HeLa cells, AMG 900 inhibits autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division without a prolonged mitotic arrest, which ultimately results in cell death. AMG 900 inhibits the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations (about 2 – 3 nM). Furthermore, AMG 900 is active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). ^[1]
• In Vivo: Oral administration of AMG 900 blocks the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. AMG 900 is broadly active in multiple xenograft models, including 3 multidrugresistant xenograft models, representing 5 tumor types. ^[1] AMG 900 exhibits a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 hours. AMG 900 is well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake has an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans are predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibits acceptable PK properties in preclinical species and is predicted to have low clearance in humans. ^[2]
• Clinical Trials: AMG 900 is now under two Phase 1 clinical trials, one is for the orally administration in adult subjects with acute leukemias and related disorders, the other is for evaluating the safety, tolerability and PK in advanced solid tumors.

Protocol

• Protocol: Kinase Assay ^[1]
• Enzyme kinase assays: Recombinant GST- or His-tagged aurora-A (TPX2), and aurora-B proteins are expressed using a baculovirus system and purified by affinity chromatography. AMG 900 activity is assessed using a standardized homogenous time-resolved fluorescence (HTRF) assay. Enzyme assays for 24 other kinases (aurora-C, p38α, TYK2, JNK2, JAK3, c-Met, VEGFR2, p38β, TIE-2, ABL (T315I), ERK1, BTK, JNK3, CDK5, PKAα, JNK1, p70S6K, PKBα, MSK1, LCK, SRC, IGFR, JAK2, and c-KIT) are done internally in a similar manner. Concentrations of enzyme, peptide substrate, and ATP in the reaction are optimized depending on the specific activity of the kinase and measured K_m values for their corresponding substrates. AMG 900 is evaluated in a kinome competition binding assay (n = 353 unique kinases) by Ambit Biosciences. AMG 900 is initially screened at a single concentration of 1000 nM, and quantitative binding constants (Kd) are determined for each positive hit (< 20="" percentage="" of="">
• Protocol: Cell Assay ^[1]
• Cell Lines: Different tumor cell lines including NCI-H460, MDA-MB231, MES-SA, NCI-H460 PTX, MDA-MB-231 PTX, MES-SA Dx5, and HCT-15.
• Concentrations: 0.5, 5.0, 50 nM
• Incubation Time: 48 hours
• Methods: Tumor cells are treated with AMG 900 for 48 hours, washed twice with complete media, and cells are replated at a density of 5000 cells per well in drug-free complete media. Cells are grown until the DMSO control wells are confluent. Cells are stained with crystal violet dye, washed with distilled water, and imaged using a digital scanner.
• Protocol: Animal Study ^[1]
• Animal Models: Nude mice bearing established HCT116 tumors
• Formulation: AM 900 is dissolved in DMSO.
• Doses: 3.75, 7.5, or 15 mg/kg
• Administration: Orally administered

References

• References: [1] Payton M, et al, Cancer Res, 2010, 70(23), 9846-9854.
• References: [2] Huang L, et al, Xenobiotica, 2011, 41(5), 400-408.

参考文献

• Payton M, et al, Cancer Res, 2010, 70(23), 9846-9854.
• Huang L, et al, Xenobiotica, 2011, 41(5), 400-408.