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Synonyms | GSK 4529 | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C44H47F2N9O5S |
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分子量 | 851.96 | CAS No. | 1089283-49-7 | |
Solubility (25°C)* | 体外 | DMSO | 170 mg/mL (199.53 mM) | |
Water | Insoluble | |||
Ethanol | Insoluble | |||
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
製品説明 | 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. |
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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 μM, 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 (~3.5 μM 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] |
キナーゼアッセイ | Kinase assays | |
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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 μM 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 μL) 50 mM HEPES (pH 7.5), 3 mM DTT, 0.1mg/mL bovine serum albumin, 1mM CHAPS, 10 mM MgCl2, 10 μM 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 μM 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. | ||
細胞アッセイ | 細胞株 | 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. |
濃度 | ~ 100 μM, stocked in DMSO at 10 mM. | |
反応時間 | 72 hours | |
実験の流れ | 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. | |
動物実験 | 動物モデル | 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. |
投薬量 | ~30 mg/kg | |
投与方法 | Orally administered |
, , Dr. Ursula Broder from Institut
, , Xuejun Jiang from Memorial Sloan-Kettering Cancer Center
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Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation [ Pharmaceuticals (Basel), 2024, 17(2)197] | PubMed: 38399413 |
Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability [ J Neurooncol, 2023, 162(1):109-118.] | PubMed: 36809604 |
Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis Type I associated High Grade Gliomas [ PLoS One, 2023, 18(2):e0277308] | PubMed: 36730269 |
SFRP4+ stromal cell subpopulation with IGF1 signaling in human endometrial regeneration [ Cell Discov, 2022, 8(1):95] | PubMed: 36163341 |
Dendrocalamus latiflorus and its component rutin exhibit glucose-lowering activities by inhibiting hepatic glucose production via AKT activation [ Acta Pharm Sin B, 2022, 12(5):2239-2251] | PubMed: 35646547 |
Cell Culture Media, Unlike the Presence of Insulin, Affect α-Synuclein Aggregation in Dopaminergic Neurons [ Biomolecules, 2022, 12(4)563] | PubMed: 35454152 |
Dexmedetomidine post-conditioning ameliorates long-term neurological outcomes after neonatal hypoxic ischemia: The role of autophagy [ Life Sci, 2021, 270:118980] | PubMed: 33428879 |
Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance [ Genome Biol, 2020, 21(1):174] | PubMed: 32669109 |
Insulin-like growth factor-I prevents hypoxia-inducible factor-1 alpha-dependent G1/S arrest by activating cyclin E/cyclin-dependent kinase2 via the phoshatidylinositol-3 kinase/AKT/forkhead box O1/Cdkn1b pathway in porcine granulosa cells†. [ Biol Reprod, 2020, 102(1):116-132] | PubMed: 31435642 |
SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors [ Cell Rep, 2019, 26(1):65-78] | PubMed: 30605687 |
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人間や獣医の診断であるか治療的な使用のためにでない。
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