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GSK1838705A

产品号 S2703 公司名称 Selleck Chemicals
CAS号 1116235-97-2 公司网站 http://www.selleckchem.com
分子式 C27H29FN8O3 电 话 (877) 796-6397
分子量 532.5693632 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 73188

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产品别名

标题
GSK1838705A
IUPAC标准名
2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide
IUPAC传统名
2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide

产品登记号

CAS号 1116235-97-2

产品性质

作用靶点 IGF-1
成盐信息 Free Base
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description GSK1838705A is a potent inhibitor of IGF-IR, IR and ALK with IC50 of 2.0 nM, 1.6 nM and 0.5 nM, respectively
Targets IGF-IR IR ALK
IC50 2 nM 1.6 nM 0.5 nM [1]
In Vitro GSK1838705A potently and ATP-competitively inhibits IGF-IR and IR with appKi values of 0.7 nM and 1.1 nM, respectively.In cells, GSK1838705A potently inhibits ligand-induced phosphorylation of IGF-IR and IR with IC50 of 85 nM and 79 nM, respectively. GSK1838705A shows the significant anti-proliferative effect in a panel of cell lines derived from solid and hematologic tumors such as L-82, SUP-M2, SK-ES and MCF-7 cells with EC50 of 24 nM, 28 nM, 141 nM and 203 nM, respectively. GSK1838705A shows an accumulation of MCF-7 and NCl-H929 cells predominantly in G1 (2N) phase of the cell cycle. GSK1838705A also inhibits ALK with Ki of 0.35 nM and supresses the proliferation of nucleophosmin (NPM)-ALK fusion cells with EC50 of 24-88 nM. GSK1838705A potently inhibits NPM-ALK phosphorylation in Karpas-299 and SR-786 cells, while has modest effect on STAT3 phosphorylation. [1]
In Vivo In NIH-3T3/LISN tumor-bearing mice, oral treatment of GSK1838705A (60 mg/kg) cause tumor growth inhibition by 77%, without significant weight loss. In COLO 205 tumor–bearing mice, inhibition of tumor growth by GSK1838705A (30 mg/kg) is 80%. Besides, the antitumor efficacy of GSK1838705A is also observed in mice bearing HT29 xenograft or BxPC3 xenograft. In mice, GSK1838705A (60 mg/kg) leads to a transient 2-fold increase in blood glucose levels by inhibiting IR signaling. GSK1838705A (60 mg/kg) inhibits the growth of established Karpas-299 xenografts with 93% tumor growth inhibition, with no effect on weights of the rats. [1]
Clinical Trials
Features GSK1838705A is a small-molecule kinase inhibitor of IGF-IR and the insulin receptor.
Protocol
Kinase Assay [1]
Kinase Assays Baculovirus-expressed glutathione S-transferase–tagged proteins encoding the intracellular domain of IGF-IR (amino acids 957–1367) and IR (amino acids 979–1382) are used for determinations of IC50s by a homogeneous time-resolved fluorescence assay. A filter binding assay is used for appKi determinations using activated IGF-IR and IR kinases. Expanded kinase-selectivity profiling of GSK1838705A is carried out by screening the compound in the KinaseProfiler panel.
Cell Assay [1]
Cell Lines L-82, SUP-M2, SK-ES and MCF-7
Concentrations 0 to 10 μM
Incubation Time 72 hours
Methods Cells are seeded in 96-well dishes, incubated overnight at 37 °C, and treated with DMSO or GSK1838705A for 72 hours. For the NIH-3T3/LISN proliferation assays, cells are seeded on collagen-coated 96-well tissue culture plates and allowed to adhere for 24 hours. The medium is replaced with serum-free medium and the cells are treated with GSK1838705A for 2 hour. Cells are incubated for 72 hours after addition of IGF-I (30 ng/mL). Cell proliferation is quantified using the CellTiter-Glo Luminescent Cell Viability Assay. IC50s are determined from cytotoxicity curves using a four-parameter curve fit software package (XLfit4).
Animal Study [1]
Animal Models L-82, SUP-M2, SK-ES and MCF-7 cells are injected s.c. into the right flank of CD1 or SCID mice.
Formulation GSK1838705A is dissolved in 20% sulfobutyl ether β-cyclodextrin (ISP; pH 3.5).
Doses ≤60 mg/kg
Administration Administered via p.o.
References
[1] Sabbatini P, et al. Mol Cancer Ther. 2009, 8(10), 2811-2820.