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AG-490 (also known as Tyrphostin B42; zinc-0255794) is a novel, potent and selective inhibitor of EGFR (epidermal growth factor receptor) with potential antitumor activities. It inhibits EGFR with an IC50 of 0.1 μM in cell-free assays, and shows 135-fold higher selectivity for EGFR over ErbB2. AG 490 also inhibits Janus kinase 2-JAK2 without inhibiting Lck, Lyn, Btk, Syk and Src.
Physicochemical Properties
| Molecular Formula | C17H14N2O3 |
| Molecular Weight | 294.30 |
| Exact Mass | 294.1 |
| CAS # | 133550-30-8 |
| Related CAS # | (E/Z)-AG490;134036-52-5 |
| PubChem CID | 5328779 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 615.2±55.0 °C at 760 mmHg |
| Melting Point | 215°C(lit.) |
| Flash Point | 325.9±31.5 °C |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C |
| Index of Refraction | 1.679 |
| LogP | 2.11 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 22 |
| Complexity | 460 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | C1=CC=C(C=C1)CNC(=O)/C(=C/C2=CC(=C(C=C2)O)O)/C#N |
| InChi Key | TUCIOBMMDDOEMM-RIYZIHGNSA-N |
| InChi Code | 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+ |
| Chemical Name | (E)-N-benzyl-2-cyano-3-(3,4-dihydroxyphenyl)acrylamide |
| Synonyms | Zinc-0255794; Tyrphostin AG490; Zinc0255794; Zinc 0255794; Tyrphostin AG-490; AG 490; AG-490; AG490; Tyrphostin AG 490 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | AG490 specifically blocks JAK2 to prevent Stat-3 from activating. JAK/Stat-3 activation is specifically inhibited by AG490. Cell viability is preserved and Stat-3 phosphorylation is reduced by more than 95% at a dosage of 10 μM. In EGF-stimulated A431 cells, 10 μM of AG490 causes a >95% drop in pStat-3 while having no effect on Stat-3 mass[1]. Strongly inhibiting the JAK3/STAT, JAK3/AP-1, and JAK3/MAPK pathways as well as their effects on cells is AG-490. In a dose-dependent manner, AG-490 eliminates IL-2-inducible [3H]thymidine incorporation with an IC50 of 25 μM. In contrast to earlier research that shown this drug triggered death in ALL cells while appearing to have no effect on the expansion of mitogen-stimulated normal T cells, AG-490 potently suppresses IL-2-mediated proliferation in T cells[2]. | ||
| ln Vivo | Type 1 diabetes (T1D) is substantially prevented by AG490 (p = 0.02, p = 0.005; at two distinct time points). In contrast to the absolute inability (0%; 0/10, p=0.003, Log-rank test) of DMSO, monotherapy with AG490 (1 mg/mouse) for newly diagnosed diabetic NOD mice significantly results in disease remission in treated animals (n=23), and sustained eugluycemia is maintained for several months after drug withdrawal[3]. In a dose-dependent manner, AG490 (1–10 µg) greatly reduces the thermal hyperalgesia caused by ʎ-carrageenan. Moreover, AG490 lessens mechanical hyperalgesia[4]. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Metabolism / Metabolites Tyrphostin B42 has known human metabolites that include Tyrphostin B42, 4-O-glucuronide and Tyrphostin B42, 3-O-glucuronide. |
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| References |
[1]. Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy. Mol Cancer Ther. 2004 Apr;3(4):459-63. [2]. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation ofIL-2-mediated T cell response. J Immunol. 1999 Apr 1;162(7):3897-904. [3]. The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice. PLoS One. 2012;7(5):e36079. [4]. Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain. Biomed Rep. 2015 Sep;3(5):703-706. |
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| Additional Infomation |
Tyrphostin B42 is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2E)-2-cyano-3-(3,4-dihydroxyphenyl)prop-2-enoic acid with the amino group of benzylamine. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an antioxidant, a STAT3 inhibitor, an anti-inflammatory agent, an apoptosis inducer and a geroprotector. It is an enamide, a monocarboxylic acid amide, a nitrile, a member of catechols and a secondary carboxamide. Tyrphostin B42 is a member of the tyrphostin family of tyrosine kinase inhibitors that inhibits epidermal growth factor receptor, blocks leukemic cell growth in vitro and in vivo by inducing programmed cell death. Inhibits the constitutive activation of STAT-3 DNA binding and IL-2-induced growth of Mycosis fungoides tumor cells. (NCI) |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (7.07 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3979 mL | 16.9895 mL | 33.9789 mL | |
| 5 mM | 0.6796 mL | 3.3979 mL | 6.7958 mL | |
| 10 mM | 0.3398 mL | 1.6989 mL | 3.3979 mL |