GSK1904529A

Information	GSK1904529A is a selective inhibitor to insulin-like growth factor-I receptor (IGF-IR) and insulin receptor (IR) with IC50 of 27 nM and 25 nM, respectively.
Targets	IGF-IR	IR
IC50	27 nM	25 nM ^[1]
In vitro	GSK1904529A is a reversible, ATP-competitive inhibitor and has enzyme-inhibitor binding values against IGF-IR and IR with K_i of 1.3 and 1.6 nM, respectively. GSK1904529A potently inhibits the ligand-induced phosphorylation of IGF-IR 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, 35, 43, 61 and 62 nM, respectively. GSK1904529A also inhibits other multiple myeloma and Ewing’s sarcoma cell lines including NCI-H929, MOLP-8, LP-1and 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 the most 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 completely inhibits IGF-IR phosphorylation ~3.5 μM in blood. GSK1904529A has been implicated in treatment of various IGF-IR-dependent tumors including prostate, colon, breast, pancreatic, ovarian, and sarcomas. ^[1]
Clinical Trials
Features

Information

GSK1904529A is a selective inhibitor to insulin-like growth factor-I receptor (IGF-IR) and insulin receptor (IR) with IC50 of 27 nM and 25 nM, respectively.

Targets

IGF-IR

IC50

27 nM

25 nM ^[1]

In vitro

GSK1904529A is a reversible, ATP-competitive inhibitor and has enzyme-inhibitor binding values against IGF-IR and IR with K_i of 1.3 and 1.6 nM, respectively. GSK1904529A potently inhibits the ligand-induced phosphorylation of IGF-IR 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, 35, 43, 61 and 62 nM, respectively. GSK1904529A also inhibits other multiple myeloma and Ewing’s sarcoma cell lines including NCI-H929, MOLP-8, LP-1and 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 the most 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 completely inhibits IGF-IR phosphorylation ~3.5 μM in blood. GSK1904529A has been implicated in treatment of various IGF-IR-dependent tumors including prostate, colon, breast, pancreatic, ovarian, and sarcomas. ^[1]

Clinical Trials

Features

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-IR (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.

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:	~ 100 μM
Incubation Time:	72 hours
Method:	Cells are seeded in 96-well plates and incubated overnight at 37℃, 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℃ for 72 hours. Cell proliferation is quantified using the CellTiter-Glo Luminescent Cell Viability Assay. IC50 values are determined.

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:

~ 100 μM

Incubation Time:

72 hours

Method:

Cells are seeded in 96-well plates and incubated overnight at 37℃, 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℃ for 72 hours. Cell proliferation is quantified using the CellTiter-Glo Luminescent Cell Viability Assay. IC50 values are determined.

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.
Formulation:	Formulated in 20% sulfobutylether-h-cyclodextrin (pH 3.5; ISP)
Dosages:	~30 mg/kg
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.

Formulation:

Formulated in 20% sulfobutylether-h-cyclodextrin (pH 3.5; ISP)

Dosages:

~30 mg/kg

Administration:

Orally administered

Molecular Weight (WM):	851.96
Formula:	C₄₄H₄₇F₂N₉O₅S
CAS No.:	1089283-49-7
Synonyms:	N/A

Molecular Weight (WM):

851.96

Formula:

C₄₄H₄₇F₂N₉O₅S

CAS No.:

1089283-49-7

Synonyms:

N/A

Dissolve in (25°C):


Storage:	2 years-20°CPowder
	1 week-4°Cin DMSO
	1 month-80°in DMSO

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Biological Activity

Protocol (Only for Reference)

Kinase Assay: [1]

Cell Assay: [1]

Animal Study:[1]

References

Chemical Information

Quality Control & MSDS

Research Area

Related Inhibitors

Secondary Antibodies

Loading Control Antibodies

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Kinase Assay: ^[1]

Cell Assay: ^[1]

Animal Study:^[1]

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