Ilginatinib maleate (NS-018 maleate; NS-018) is an orally bioavailable, small molecule inhibitor of Janus-associated kinase 2 (JAK2) and Src-family kinases, with potential antineoplastic activity. It inhibits JAK2 with an IC50 of 0.72 nM, and exhibits 46-, 54-, and 31-fold selectivity for JAK2 over JAK1 (IC50, 33 nM), JAK3 (IC50, 39 nM), and Tyk2 (IC50, 22 nM). JAK2/Src inhibitor NS-018 competes with ATP for binding to JAK2 as well as the mutated form JAK2V617F, thereby inhibiting the activation of JAK2 and downstream molecules in the JAK2/STAT3 (signal transducer and activator of transcription 3) signaling pathway that plays an important role in normal development, particularly hematopoiesis. In addition, NS-018 inhibits the Src family tyrosine kinases. This eventually leads to the induction of tumor cell apoptosis.
Physicochemical Properties
| Molecular Formula | C25H24FN7O4 |
| Molecular Weight | 505.5010 |
| Exact Mass | 505.187 |
| Elemental Analysis | C, 59.40; H, 4.79; F, 3.76; N, 19.40; O, 12.66 |
| CAS # | 1354799-87-3 |
| Related CAS # | Ilginatinib;1239358-86-1;Ilginatinib hydrochloride;1239358-85-0 |
| PubChem CID | 56599590 |
| Appearance | Light yellow to yellow solid powder |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 37 |
| Complexity | 620 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | FC1C([H])=C([H])C(=C([H])C=1[H])[C@]([H])(C([H])([H])[H])N([H])C1=C([H])C(=C([H])C(N([H])C2C([H])=NC([H])=C([H])N=2)=N1)C1C([H])=NN(C([H])([H])[H])C=1[H].O([H])C(/C(/[H])=C(/[H])\C(=O)O[H])=O |
| InChi Key | OVAGJAAQMBYZDS-FXSDFHGDSA-N |
| InChi Code | InChI=1S/C21H20FN7.C4H4O4/c1-14(15-3-5-18(22)6-4-15)26-19-9-16(17-11-25-29(2)13-17)10-20(27-19)28-21-12-23-7-8-24-21;5-3(6)1-2-4(7)8/h3-14H,1-2H3,(H2,24,26,27,28);1-2H,(H,5,6)(H,7,8)/b;2-1-/t14-;/m0./s1 |
| Chemical Name | (Z)-but-2-enedioic acid;6-N-[(1S)-1-(4-fluorophenyl)ethyl]-4-(1-methylpyrazol-4-yl)-2-N-pyrazin-2-ylpyridine-2,6-diamine |
| Synonyms | NS-018; NS018; NS 018; NS-018 maleate; Ilginatinib maleate; |
| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 | Ilginatinibmaleate (NS-018maleate) is 46, 54, and 31 times more selective for JAK2 than JAK1 (IC50, 33 nM), JAK3 (IC50, 39 nM), and Tyk2 (IC50, 22 nM). is a highly active JAK2 inhibitor with an IC50 of 0.72 nM. Additionally, lignotinibmaleate mildly inhibits ABL and FLT3, with 45- and 90-fold selectivity for JAK2, and inhibits Src family kinases, including SRC and FYN. With an IC50 of 11–120 nM, ilginatinibmaleate exhibits strong inhibitory activity against constitutively activated JAK2 (JAK2V617F, MPLW515L mutant cell lines, and the TEL–JAK2 fusion gene), but not against the majority of other hematopoietic cell lines. minimally cytotoxically activates JAK2 [1]. When used in myelodysplastic syndromes (MDS), ilginatinibmaleate (0.5 μM) primarily suppresses the development of colony-forming unit granulocytes/macrophages (CFU-GM) produced from bone marrow mononuclear cells (BMMNC). In MDS patients' CFU-GM-forming cells, ilginatinibmaleate (1 μM) suppresses the phosphorylation of STAT3, a downstream kinase of JAK2 [2]. |
| ln Vivo | In the mouse Ba/F3-JAK2V617F illness model, ilginatinibmaleate (NS-018maleate) (12.5, 25, 50, 100 mg/kg, oral) can successfully reduce splenomegaly and increase the length of time that mice survive [1]. In JAK2V617F transgenic mice, ilginatinib maleate (25, 50 mg/kg, oral) dramatically lowers leukocytosis, hepatosplenomegaly, and extramedullary hematopoiesis, enhances nutritional status, and increases survival [1]. |
| References |
[1]. Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J. 2011 Jul;1(7):e29. [2]. NS-018, a selective JAK2 inhibitor, preferentially inhibits CFU-GM colony formation by bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients. Leuk Res. 2014 May;38(5):619-24. |
Solubility Data
| Solubility (In Vitro) |
DMSO : ≥ 30 mg/mL (~59.35 mM) H2O : ~1 mg/mL (~1.98 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.95 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 25.0 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: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9782 mL | 9.8912 mL | 19.7824 mL | |
| 5 mM | 0.3956 mL | 1.9782 mL | 3.9565 mL | |
| 10 mM | 0.1978 mL | 0.9891 mL | 1.9782 mL |