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1110813-31-4 分子结构
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(2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide

ChemBase编号:73216
分子式:C24H25ClFN5O2
平均质量:469.9390032
单一同位素质量:469.16808097
SMILES和InChIs

SMILES:
C(/C=C/C(=O)Nc1c(cc2c(c1)c(ncn2)Nc1cc(c(cc1)F)Cl)OC)N1CCCCC1
Canonical SMILES:
COc1cc2ncnc(c2cc1NC(=O)/C=C/CN1CCCCC1)Nc1ccc(c(c1)Cl)F
InChI:
InChI=1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+
InChIKey:
LVXJQMNHJWSHET-AATRIKPKSA-N

引用这个纪录

CBID:73216 http://www.chembase.cn/molecule-73216.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
(2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide
IUPAC传统名
(2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide
别名
PF299804
CAS号
1110813-31-4
PubChem SID
162038136
PubChem CID
11511120

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S2727 external link 加入购物车 请登录
数据来源 数据ID
PubChem 11511120 external link

理论计算性质

理论计算性质

JChem
Acid pKa 12.4996195  质子受体
质子供体 LogD (pH = 5.5) 1.7521503 
LogD (pH = 7.4) 3.5269334  Log P 4.707501 
摩尔折射率 129.9123 cm3 极化性 49.17349 Å3
极化表面积 79.38 Å2 可自由旋转的化学键
里宾斯基五规则 true 

分子性质

分子性质

安全信息 药理学性质 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
作用靶点
EGFR(HER) expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S2727 external link
Biological Activity
Description PF299804 is a potent, irreversible pan-ErbB inhibitor against ErbB1, ErbB2 and ErbB4 with IC50 of 6 nM, 45.7 nM and 73.7 nM, respectively.
Targets ErbB1 ErbB2 ErbB4
IC50 6 nM 45.7 nM 73.7 nM [1]
In Vitro PF299804 is a specific inhibitor of the ERBB family of kinases. PF299804 inhibits EGFR signaling and induces apoptosis in the EGFR T790M–containing H3255 GR cell line. PF299804 is effective in gefitinib-sensitive and gefitinibresistant NSCLC cell lines. PF299804 inhibits the growth of H3255 and HCC827 cells engineered to express EGFR T790M. PF299804 inhibits EGFR phosphorylation in the presence of the T790M mutation. [1] PF-299804 is believed to irreversibly inhibit ERBB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of ERBB family members. [2] PF299804 shows significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it has lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF299804 induces apoptosis and G1 arrest and inhibits phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF299804 also blocks EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. [3] A recent research uses forty-seven human breast cancer and immortalized breast epithelial lines to evaluate the inhibition effects of PF299804, the results indicate PF299804 preferentially inhibits growth of HER-2-amplified breast cancer cell lines than nonamplified lines (RR = 3.39, p < 0.0001).="" pf299804="" reduces="" the="" phosphorylation="" of="" her2,="" egfr,="" her4,="" akt,="" and="" erk="" in="" the="" majority="" of="" sensitive="" lines.="" pf299804="" exerts="" its="" anti-proliferative="" effect="" through="" a="" combined="" g0/g1="" arrest="" and="" an="" induction="" of="" apoptosis.="">[4]
In Vivo Orally administered PF299804 effectively inhibits growth of HCC827 Del/T790M xenografts. [1] Low oral administration of PF-299804 (15mg/kg) causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/ or overexpress ERBB family members or contain the double mutation (L858R/T790M) in ERBB1 (EGFR) associated with resistance to gefitinib and erlotinib. [2]
Clinical Trials PF299804 is now under the Phase 2 clinical trial for the safety and efficacy in patients with recurrent glioblastoma with EGFR amplification or presence of EGFRVIII mutation.
Features
Combination Therapy
Description Combined use of PF299804 with 5-Fu or ciplatin induces a significant growth delay of N87 human gastric cancer xenograft model. [2]
Protocol
Kinase Assay [1]
ELISA-Based ERBB Kinase Assay The ERBB1, ERBB 2, and ERBB4 cytoplasmic fusion proteins are made by cloning the ERBB1 sequence (Met-668 to Ala-1211), ERBB2 (Ile-675 to Val-1256), and ERBB4 sequence (Gly-259 to Gly-690) into the baculoviral vector pFastBac using PCR. Proteins are expressed in baculovirusinfected Sf9 insect cells as GST fusion proteins. The proteins are purified by affinity chromatography using glutathione sepharose beads. Inhibition of ERBB tyrosine kinase activity is assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 μM ATP, PF299804 or vehicle control, and 1-5 nM GST-erbB per 50 μL of reaction mixture) are run in 96-well plates coated with 0.25 mg/mL poly-Glu-Tyr. The reactions are incubated for 6 minutes at room temperature while being shaken. Kinase reactions are stopped by removal of the reaction mixture, and then the wells are washed with wash buffer (0.1% Tween 20 in PBS). Phosphorylated tyrosine residues are detected by adding 0.2 μg/mL antiphosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to horseradish peroxidase (HRP) diluted in PBS containing 3% BSA and 0.05% Tween 20 for 25 minutes while being shaken at room temperature. The antibody is removed, and plates are washed in wash buffer. HRP substrate (SureBlue3,3?,5,5?-tetramethyl benzidine or TMB) is added (50 μL per well) and incubated for 10-20 minutes while it is shaken at room temperature. The TMB reaction is stopped with the addition of 50 μL of stop solution (0.09 N H2SO4). The signal is quantified by measuring absorbance at 450 nm. IC50 values are determined for PF299804 using the median effect method.
Cell Assay [1]
Cell Lines Various NSCLC cell lines
Concentrations 0-20 nM
Incubation Time 72 hours
Methods Growth and inhibition of growth is assessed by 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. This assay, a colorimetric method fordetermining the number of viable cells, is based on the bioreduction of MTS by cells to a formazan product that is soluble in cell culture medium, can be detected spectrophotometrically. The cells are exposed totreatment for 72 hours, and the number of cells used per experiment is determined empirically. All experimental points are set up in 6 to 12 wells, and all experiments are repeated at least thrice. The data are graphically displayed using GraphPad Prism version 3.00 for Windows (GraphPad Software). The curves are fitted using a nonlinear regression model with a sigmoidal dose response.
Animal Study [1]
Animal Models HCC827-GFP or HCC827-Del/T790M lung cancer cells (in 0.2 mL of PBS) are inoculated s.c. into the lower-right quadrant of the flank of nude mice
Formulation PF299804 is dissolved in DMSO in 10 mM at -20 °C.
Doses 10 mg/kg
Administration Administered via oral gavage
References
[1] Engelman JA, et al, Cancer Res, 2007, 67(24), 11924-11932.
[2] Gonzales AJ, et al, Mol Cancer Ther, 2008, 7(7), 1880-1889.
[3] Nam HJ, et al, Mol Cancer Ther, 2012, 11(2), 439-451.
[4] Kalous O, et al, Mol Cancer Ther, 2012, Jul 3.

参考文献

参考文献

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