AG-490

ArtNr	S1143-10000
Hersteller	Selleckchem
CAS-Nr.	133550-30-8
Menge	10 g
Quantity options	10 mg 100 mg 1 g 10 g 10 mM/1 ml 25 mg 300 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Neural Lineage Markers Neural Transcription Factors Targets for Rodent Neurosciences Aging & Neurological Disorders Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Bladder Cancer Breast Cancer Heart & Blood Cancer Lymphatic System Cancer Bone Cancer
Typ	Inhibitors
Specific against	other
Smiles	C1=CC=C(C=C1)CNC(=O)C(=CC2=CC(=C(C=C2)O)O)C#N
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	Tyrphostin B42,Zinc02557947
Similar products	AG-490
Lieferbar
Manufacturer - Targets	ERBB2, JAK2, EGFR
Storage Conditions	2 years -80 in solvent
Molecular Weight	294, 3
Administration	Continuous pump infusion supplemented with daily intraperitoneal injections
Animal Models	SCID mice intravenously injected with ALL cells
Cell lines	Pre-B ALL
Concentrations	Dissolved in DMSO, final concentrations ca. 50 uM
Dosages	0.85 mg + 0.5 mg daily
Formulation	Dissolved in DMSO
IC50	0.1 uM, 0.1 uM, 0.1 uM, 0.1 uM, 0.1 uM, 0.1 uM
In vitro	AG-490 inhibits HER-2 driven cell proliferation with IC50 of 3.5 uM. [1] Corresponding to the specific dose-dependent inhibition of constitutively activated JAK2 in pre-B acute leukemia (ALL) cells, AG-490 (5 uM) almost completely blocks the growth of all ALL cells by inducing programmed cell death, with no deleterious effect on normal hematopoiesis. AG-490 does not inhibit the activities of Lck, Lyn, Btk, Syk, and Src. [2] AG-490 (60-100 uM) blocks the constitutive activation of Stat3sm, and inhibits spontaneous as well as interleukin 2-induced growth of mycosis fungoides (MF) tumor cells with IC50 values of 75 uM and 20 uM, respectively. [3] AG-490 potently inhibits IL-2-mediated human T cell growth with an IC50 of 25 uM by blocking the activities of JAK3 and STAT5a/b. [4] Although AG-490 alone has no effect on proliferation of FDrv210H cells at a concentration of 5 uM, AG-490 can synergize with STI571 to enhance its inhibitory effect on p210bcr-abl driven proliferation. [5] AG-490 significantly inhibits the constitutive activation of Stat3 in MOPC, MPC11, and S194 cells, leading to dramatic dose-dependent apoptosis. [6] AG-490 (100 uM) inhibits Akt phosphorylation, inhibits the activation of nuclear factor-kappaB, and causes the activation of GSK-3beta, leading to the reduction of c-Myc. AG-490 (50 uM) can induce apoptosis of imatinib-resistant BaF3 cells expressing T315I and E255K mutants of Bcr-Abl. [7] AG-490 at 30 uM inhibits not only Epo-induced phosphorylation of wild-type JAK2 but also constitutive phosphorylation of the JAK2 V617F mutant. AG-490 also potently inhibits cytokine-independent cell growth induced by the JAK2 V617F mutant in BaF3 cells. [8]
In vivo	Administration of AG-490 drastically reduces the numbers of CD45+ and HLA-DR+ cells from 48 % and 46% in bone marrow of untreated mice, as well as 38% and 22% in the spleen of untreated mice to undetectale levels. [2] In vivo administration of AG-490 causes murine myeloma tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-gamma production by lymphocytes. [6] Consistent with the in vitro blocking of JAK2 V617F mutant activity, AG-490 treatment at 0.5 mg/day for 10 days effectively inhibits JAK2 V617F mutant-induced tumorigenesis and tumor cell invasion in nude mice. [8] Combined therapy with AG-490 and IL-12 induces greater antitumor effects than either agent alone in a murine myeloma tumor model. [6]
Incubation Time	16 hours
Kinase Assay	In vitro kinase autophosphorylation, AG-490 is dissolved in DMSO 10%-H2O-ethanol 45%. Crude membrane extracts (0.125 ug/mL) are preactivated with EGF (20 nM) in 50 mM HEPES buffer, pH 7.6, and 125 mM NaCl, for 15 minutes at 4 C. Autophosphorylation activity of EGFR or ErbB2 kinase is assayed at 4 C for 30 seconds in V-shaped 96-well plates. Membrane extracts (8 uL) are added to each well containing reaction mixture (12 uL, 50mM, HEPES, pH 7.4, 125 mM NaCl, 12 mM M8Ac2, 2 mM MnCl2, 1 mM NaVO3, 1 uM ATP, and 1 uCi[gamma-32P]ATP, final concentrations) and increasing concentrations of AG-490 (4 uL). After termination by addition of hot sample buffer, the samples are run on a 6% SDS-polyacrylamide gel electrophoresis minigel, the gels dried, and autoradiography performed during the linear exposure time period. The receptor bands are scanned densitrometrically, and the results analyzed by the Ez-Fit program. For the analysis of autophosphorylation of JAK2, JAK2 is immunoprecipitated by using anti-JAK2 antibody from lysates of G2 cells pretreated for 16 hours with increasing concentrations of AG-490 (0-50 uM). Immune complexes are then immunoblotted with anti-phosphotyrosine antibody. A dose-dependent inhibition of in vitro kinase activity is demonstrated by assessing JAK2 autophosphorylation.
Method	Cells are exposed to different concentrations of AG-490 for 16 hours. For the determination of cell proliferation, [3H]tymidine (1 Ci) is added 6 hours or more before the cultures are terminated. Cells are then collected and samples counted in a liquid scintillation counter.
Solubility (25C)	DMSO 59 mg/mL, Water <1 mg/mL, Ethanol 6 mg/mL
Information	AG-490 is an inhibitor of EGFR with IC50 of 0.1 μM in cell-free assays, 135-fold more selective for EGFR versus ErbB2, also inhibits JAK2 with no activity to Lck, Lyn, Btk, Syk and Src.
Chemical Name	(E)-N-benzyl-2-cyano-3-(3, 4-dihydroxyphenyl)acrylamide

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