AG-490

Tyrphostin AG490 is a JAK-2 specific inhibitor, which inhibits phosphorylation of EGFR and signal transducer and activator of transcription 3 [STAT-3], and subsequently reduce invasion and adhesion potential of malignant cells. The hematopoietic cancer c-Kit+, Jak-2+ and non hematopoietic tumors c-Kit+, HER-2+, JAK-2+ can be inhibited by the chemosensitizing agent AG490 causing programmed cell death.

Product information

CAS Number: 133550-30-8

Molecular Weight: 294.30

Formula: C17H14N2O3

Synonym:

AG 490

AG490

Tyrphostin AG 490

Chemical Name: (E)-N-benzyl-2-cyano-3-(3, 4-dihydroxyphenyl)acrylamide

Smiles: N#C/C(=C\C1=CC(O)=C(O)C=C1)/C(=O)NCC1C=CC=CC=1

InChiKey: TUCIOBMMDDOEMM-RIYZIHGNSA-N

InChi: InChI=1S/C17H14N2O3/c18-10-14(8-13-6-7-15(20)16(21)9-13)17(22)19-11-12-4-2-1-3-5-12/h1-9,20-21H,11H2,(H,19,22)/b14-8+

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 58 mg/mL(197.07 mM).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

AG-490 inhibits HER-2 driven cell proliferation with IC50 of 3.5 μM. Corresponding to the specific dose-dependent inhibition of constitutively activated JAK2 in pre-B acute leukemia (ALL) cells, AG-490 (5 μM) 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. AG-490 (60-100 μM) 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 μM and 20 μM, respectively. AG-490 potently inhibits IL-2-mediated human T cell growth with an IC50 of 25 μM by blocking the activities of JAK3 and STAT5a/b. Although AG-490 alone has no effect on proliferation of FDrv210H cells at a concentration of 5 μM, AG-490 can synergize with STI571 to enhance its inhibitory effect on p210bcr-abl driven proliferation. AG-490 significantly inhibits the constitutive activation of Stat3 in MOPC, MPC11, and S194 cells, leading to dramatic dose-dependent apoptosis. AG-490 (100 μM) inhibits Akt phosphorylation, inhibits the activation of nuclear factor-κB, and causes the activation of GSK-3β, leading to the reduction of c-Myc. AG-490 (50 μM) can induce apoptosis of imatinib-resistant BaF3 cells expressing T315I and E255K mutants of Bcr-Abl. AG-490 at 30 μM 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.

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. In vivo administration of AG-490 causes murine myeloma tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-γ production by lymphocytes. 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. Combined therapy with AG-490 and IL-12 induces greater antitumor effects than either agent alone in a murine myeloma tumor model.

References:

1. Gazit A, et al. J Med Chem, 1991, 34(6), 1896-1907.
2. Meydan N, et al. Nature, 1996, 379(6566), 645-648.
3. Nielsen M, et al. Proc Natl Acad Sci U S A, 1997, 94(13), 6764-6769.
4. Kirken RA, et al. J Leukoc Biol, 1999, 65(6), 891-899.
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7. Samanta AK, et al. Cancer Res, 2006, 66(13), 6468-6472.
8. Abe M, et al. Int Immunopharmacol, 2009, 9(7-8), 870-877.

Products are for research use only. Not for human use.