2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]-N-methylacetamide

• ChemBase编号: 72885
• 分子式: C23H25ClFN5O3
• 平均质量: 473.9277032
• 单一同位素质量: 473.16299559
• SMILES: c1(c(cc2c(c1)c(ncn2)Nc1c(F)c(ccc1)Cl)OC)OC1CCN(CC1)CC(=O)NC
• Canonical SMILES: CNC(=O)CN1CCC(CC1)Oc1cc2c(ncnc2cc1OC)Nc1cccc(c1F)Cl
• InChI: InChI=1S/C23H25ClFN5O3/c1-26-21(31)12-30-8-6-14(7-9-30)33-20-10-15-18(11-19(20)32-2)27-13-28-23(15)29-17-5-3-4-16(24)22(17)25/h3-5,10-11,13-14H,6-9,12H2,1-2H3,(H,26,31)(H,27,28,29)
• InChIKey: DFJSJLGUIXFDJP-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]-N-methylacetamide
• IUPAC传统名: 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]-N-methylacetamide
• 别名: AZD8931

登记号

• CAS号: 848942-61-0
• PubChem SID: 162037806
• PubChem CID: 11488320

理论计算性质

• Acid pKa: 13.53239
• 质子受体: 7
• 质子供体: 2
• LogD (pH = 5.5): 1.2968376
• LogD (pH = 7.4): 2.6736393
• Log P: 2.812373
• 摩尔折射率: 123.8024 cm^3
• 极化性: 48.292267 Å^3
• 极化表面积: 88.61 Å^2
• 可自由旋转的化学键: 7
• 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: EGFR; HER2

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2192

Research Area

• Description: Cancer

Biological Activity

• Description: AZD8931 is a reversible, ATP competitive inhibitor of EGFR, ErbB2 and ErbB3 with IC50 of 4 nM, 3 nM and 4 nM, respectively.
• Targets:

  EGFR

  ;

  ErbB2

  ;

  ErbB3

• IC50:

  4 nM

  ;

  3 nM

  ;

  4 nM ^[1]

• In Vitro: AZD8931 shows different potency to NSCLC and SCCHN cell lines. AZD8931 has high sensitivity to PC-9 cells (EGFR activating mutation) with GI50 of 0.1 nM and low activity to NCI-1437 cells with GI50 above 10 μM. AZD8931 exhibits more potency against phospho-EGFR, phospho-erbB2 and phospho-erbB3 than either lapatinib or gefitinib in PE/CA-PJ41, PE/CA-PJ49, DOK and FaDu cells. ^[1]
• In Vivo: AZD8931 reveals antitumor activity in BT474c, Calu-3, LoVo, FaDu and PC-9 xenografts. AZD8931 could reduce p-Akt, Ki67 expression and p-ERK in BT474c xenografts following acute treatment. AZD8931 also causes induction of the M30 apoptosis marker. Furthermore, AZD8931 shows greater proapoptotic effect compared with gefitinib and lapatinib in LoVo xenografts. ^[1]
• Clinical Trials: Currently under Phase I clinical trial in Japanese patients with advanced solid malignancies.

Combination Therapy

• Description: Combined with paclitaxel, AZD8931 is currently under Phase I clinical trial in Japanese female patients with advanced breast cancer.

Protocol

• Protocol: Kinase Assay ^[1]
• Isolated kinase assays: The intracellular kinase domains of human EGFR and erbB2 are cloned and expressed in the baculovirus/Sf21 system. The inhibitory activity of AZD8931 is determined with ATP at Km concentrations (0.4 mM for erbB2 and 2 mM for EGFR) using the ELISA method.
• Protocol: Cell Assay ^[1]
• Cell Lines: Head and neck tumor cell lines (KYSE-30, OE21, PE/CA-PJ15, PE/CA-PJ34 (clone C12), PE/CA-PJ41 (clone D2), PE/CA-PJ49, DOK, Detroit562, RPMI2650, SCC-4, SCC-9, SCC-25, CAL 27, SW579, FaDu, Hs 840.T, KB, KYSE-450, and HEp-2, HN5) and NSCLC cell lines (PC-9, Calu-3, NCI-H2073, NCI-H1623, NCI-H522, NCI-H2085, NCI-H2030, NCI-H1703, NCI-H2291, NCI-H2135, NCI-H1975, NCI-H23, NCI-H1650, NCI-H1437, NCI-H3255, and NCI-H1666)
• Concentrations: 0.001-10 μM
• Incubation Time: 96 hours
• Methods:

  To determine the antiproliferative activity against cell lines grown in vitro, AZD8931 is tested in a panel of NSCLC and SCCHN cell lines. Cells are incubated for 96 hours with AZD8931 (0.001-10 μM). Viable cell number is determined by 4 hours of incubation with MTS Colorimetric Assay reagent and absorbance measured at 490 nm on a spectrophotometer.

• Protocol: Animal Study ^[1]
• Animal Models: BT474c, Calu-3, LoVo, FaDu and PC-9 xenografts in Swiss nude or severe combined immunodeficient (Charles River) mice.
• Formulation: Suspended in a 1% (v/v) solution of polyoxyethylenesorbitan monooleate (Tween 80) in deionized water
• Doses: 6.25-50 mg/kg
• Administration: Gavage

References

• References: [1] Hickinson DM, et al. Clin Cancer Res, 2010, 16(4), 1159-1169.

参考文献

• Hickinson DM, et al. Clin Cancer Res, 2010, 16(4), 1159-1169.