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GSK1904529A

GSK1904529A

Item no.	S1093-5000
Manufacturer	Selleckchem
CASRN	1089283-49-7
Amount	5 g
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 50 mg 5 g
Category	Oncology Neuroscience Metabolism Diabetes Cholesterol & Lipid Metabolism Regulation of Appetite Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Skin Cancer Colorectal Cancer Breast Cancer Lymphatic System Cancer Uterine, Ovarian & Cervical Cancer
Type	Inhibitors
Specific against	other
Smiles	CCC1=CC(=C(C=C1N2CCC(CC2)N3CCN(CC3)S(=O)(=O)C)OC)NC4=NC=CC(=N4)C5=C(N=C6N5C=CC=C6)C7=CC(=C(C=C7)OC)C(=O)NC8=C(C=CC=C8F)F
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	GSK 4529
Similar products	GSK1904529A
Available
Storage Conditions	2 years -80 in solvent
Molecular Weight	851, 96
Administration	Orally administered
Animal Models	NIH-3T3/LISN, COLO 205, HT29, and BxPC3 cells are implanted s.c. into the right flank of 8- to 10-wk-old female nu/nu CD-1athymic mice.
Cell lines	Tumor cell lines including multiple myeloma, ewing's sarcoma, askin's tumor, colon, breast, anaplastic large cell lymphoma, lung, cervix, head and neck, prostate and ovary.
Concentrations	ca. 100 uM, stocked in DMSO at 10 mM.
Dosages	ca.30 mg/kg
Formulation	Formulated in 20% sulfobutylether-h-cyclodextrin (pH 3.5, ISP)
IC50	27 nM, 27 nM, 27 nM, 27 nM, 27 nM, 27 nM
In vitro	GSK1904529A is a reversible, ATP-competitive inhibitor and has enzyme-inhibitor binding values against IGF-1R and IR with Ki of 1.6 nM and 1.3 nM, respectively. GSK1904529A potently inhibits the ligand-induced phosphorylation of IGF-1R and IR at concentrations above 0.01 uM, followed by blocking downstream signaling (AKT, IRS-1, and ERK). GSK1904529A potently inhibits NIH-3T3/LISN, TC-71, SK-N-MC, SK-ES RD-ES cells with IC50 of 60 nM, 35 nM, 43 nM, 61 nM and 62 nM, respectively. GSK1904529A also inhibits other multiple myeloma and Ewing's sarcoma cell lines including NCI-H929, MOLP-8, LP-1 and KMS-12-BM etc. GSK1904529A induces cell cycle arrest at the G1 phase in cell lines COLO 205, MCF-7, and NCI-H929, which are sensitive to GK1904529A. [1]
In vivo	GSK1904529A indicates 98% tumor growth inhibition in NIH-3T3/LISN tumor-bearing mice at a dose of 30 mg/kg (orally, twice-daily) and 75% in COLO 205 xenografts mice (once daily). Among HT29 and BxPC3 xenografts, GSK1904529A produces moderate tumor growth inhibition with no side effects at a dose of 30 mg/kg. Meanwhile, GSK1904529A shows minimal effects on blood glucose levels. GSK1904529A (ca.3.5 uM in blood) completely inhibits IGF-1R phosphorylation. GSK1904529A has been implicated in treatment of various IGF-1R-dependent tumors including prostate, colon, breast, pancreatic, ovarian, and sarcomas. [1]
Incubation Time	72 hours
Kinase Assay	Kinase assays, GSK1904529A is dissolved in DMSO as stock solution at 10 mM. Baculovirus-expressed glutathione S-transferase-tagged proteins encoding the intracellular domain of IGF-1R (amino acids 957-1367) and IR (amino acids 979-1382) are used for determination of IC50. Kinases are activated by preincubating the enzyme (2.7 uM final concentration) in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1mg/mL bovine serum albumin, and 2 mM ATP. GSK1904529A is diluted in DMSO and dispensed into the assay plates (100 nL/well). Kinase reactions contained (in 10 uL) 50 mM HEPES (pH 7.5), 3 mM DTT, 0.1mg/mL bovine serum albumin, 1mM CHAPS, 10 mM MgCl2, 10 uM ATP, 500 nM substrate peptide (biotin-aminohexylAEEEEYMMMMAKKKK-NH2, QPC), and 0.5 nM activated enzyme. Reactions are stopped after 1 hour at room temperature with 33 uM EDTA. Peptide phosphorylation is measured by time-resolved fluorescence resonance energy transfer with 7 nM streptavidin Surelight allophycocyanin and 1nM europium-conjugated phosphotyrosine antibodies. Plates are read in a multilabel reader.
Method	Cells are seeded in 96-well plates and incubated overnight at 37 C, and treated with various concentrations of GSK1904529A for 72 hours. For the NIH-3T3/LISN, cells are seeded on collagen-coated 96-well tissue culture plates and allowed to adhere for 24 hours. The tissue culture medium is replaced with serum-free medium and the cells are treated with DMSO or GSK1904529A for 2 hours. IGF-I (30 ng/mL) is added and the cells are incubated at 37 C for 72 hours. Cell proliferation is quantified using the CellTiter-Glo Luminescent Cell Viability Assay. IC50 values are determined.
Solubility (25C)	DMSO 170 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	GSK1904529A (GSK 4529) is a selective inhibitor of IGF-1R and IR with IC50 of 27 nM and 25 nM in cell-free assays, >100-fold more selective for IGF-1R/InsR than Akt1/2, Aurora A/B, B-Raf, CDK2, EGFR etc.
Chemical Name	N-(2, 6-difluorophenyl)-5-(3-(2-(5-ethyl-2-methoxy-4-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-yl)H-imidazo[1, 2-a]pyridin-2-yl)-2-methoxybenzamide

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