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| Targets |
The primary target of NS-018 maleate is Janus-associated kinase 2 (JAK2), a non-receptor tyrosine kinase that plays a central role in cytokine signaling and hematopoiesis. JAK2 is activated by cytokines such as erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, and its constitutive activation due to the JAK2V617F mutation is a hallmark of myeloproliferative neoplasms. NS-018 maleate acts as a highly potent, ATP-competitive inhibitor of JAK2 with an IC50 of 0.72 nM. It demonstrates 30-50-fold selectivity for JAK2 over other JAK family members, including JAK1 (IC50 = 33 nM), JAK3 (IC50 = 39 nM), and TYK2 (IC50 = 22 nM). In addition to JAK2, NS-018 maleate inhibits Src-family kinases, including SRC and FYN. This unique selectivity profile—potent JAK2 inhibition combined with Src-family kinase targeting while sparing JAK1—preserves platelet and erythrocyte counts in preclinical models.
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| 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].
In vitro, NS-018 maleate is a highly potent JAK2 inhibitor with an IC50 of 0.72 nM. It demonstrates 30-50-fold selectivity for JAK2 over other JAK family members (JAK1, JAK3, TYK2) and also inhibits Src-family kinases (SRC, FYN). The compound shows 4.3-fold selectivity for the JAK2V617F mutant over wild-type JAK2, with IC50 values of 11-120 nM in mutant-driven cell lines. This mutant selectivity is particularly important for the treatment of MPNs, as the JAK2V617F mutation is the most common genetic abnormality in these diseases. NS-018 maleate shows potent antiproliferative activity against cell lines expressing constitutively activated JAK2. |
| 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].
In vivo, NS-018 maleate demonstrates significant efficacy in animal models of MPNs. It markedly reduces splenomegaly and prolongs the survival of mice inoculated with Ba/F3 cells harboring the JAK2V617F mutation. In JAK2V617F transgenic mice, NS-018 maleate significantly reduces leukocytosis, hepatosplenomegaly, and extramedullary hematopoiesis, improves nutritional status, and prolongs survival. The compound's oral bioavailability and potent in vivo efficacy support its continued development as a therapeutic agent for JAK2-driven malignancies. A Phase 1 trial reported a 47% spleen response in prior JAK inhibitor-treated patients, and a Phase 2b trial is enrolling patients with platelet counts below 50,000/µL. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NS-018 maleate involve kinase activity assays using purified JAK2 enzyme or cell lysates. The compound's inhibitory activity is measured by monitoring the phosphorylation of a substrate peptide or protein in the presence of ATP. IC50 values are determined from dose-response curves generated by plotting inhibitor concentration against residual kinase activity. Selectivity profiling against a panel of other kinases, including JAK1, JAK3, TYK2, and Src-family kinases, is performed to assess the compound's specificity. These assays confirm that NS-018 maleate is a potent and selective JAK2 inhibitor with activity against Src-family kinases.
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| Cell Assay |
In vitro cellular assays for NS-018 maleate are conducted in hematopoietic cell lines expressing constitutively activated JAK2, including those with the JAK2V617F mutation. Cells are treated with varying concentrations of NS-018 maleate, and cell proliferation is measured using assays such as MTT, CellTiter-Glo, or colony formation assays. Apoptosis can be evaluated by measuring caspase activation, annexin V staining, or PARP cleavage. JAK2 phosphorylation and downstream signaling (e.g., STAT3, STAT5) are assessed by western blotting using phospho-specific antibodies. These assays confirm that NS-018 maleate engages its target in a cellular context and produces the expected anti-proliferative effects in JAK2-driven cells.
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| Animal Protocol |
In vivo animal studies for NS-018 maleate are conducted in mouse models of MPNs, including JAK2V617F transgenic mice and mice inoculated with Ba/F3 cells harboring the JAK2V617F mutation. Animals are administered the compound orally, and disease progression is monitored by measuring spleen size, white blood cell counts, and overall survival. Histological examination of spleen, liver, and bone marrow is performed to assess the extent of extramedullary hematopoiesis and disease burden. These studies confirm that NS-018 maleate is effective in vivo and support its continued development for the treatment of MPNs.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NS-018 maleate indicate that it has a molecular weight of 505.5 and a molecular formula of C25H24FN7O4. The compound is orally bioavailable, enabling convenient administration for in vivo studies. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. The compound is supplied as a lyophilized powder with ≥98% purity, QC-validated by NMR/HPLC/MS for reproducible in vivo and in vitro studies. For storage, the powder should be kept at 0-4°C for short term (days to weeks) or -20°C for long term (months to years).
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| Toxicity/Toxicokinetics |
The toxicological profile of NS-018 maleate is derived from preclinical and clinical studies. As a JAK2 inhibitor, potential on-target toxicities include thrombocytopenia, anemia, and immunosuppression, which are well-documented class effects of JAK inhibitors. However, NS-018 maleate's selectivity for JAK2 over JAK1 is designed to minimize these toxicities, as JAK1 inhibition is associated with immunosuppression and increased risk of infections. In preclinical models, NS-018 maleate preserves platelet and erythrocyte counts, addressing a significant unmet need in MPN patients with severe thrombocytopenia. In Phase 1 trials, the compound was generally well-tolerated, with a 47% spleen response rate observed in prior JAK inhibitor-treated patients. Comprehensive toxicology studies would be required for full clinical development.
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| References |
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| Additional Infomation |
NS-018 maleate is the maleate salt form of the highly potent and orally bioavailable JAK2 inhibitor NS-018. It is also known as Ilginatinib maleate. The compound has an IC50 of 0.72 nM for JAK2 and demonstrates 30-50-fold selectivity for JAK2 over JAK1, JAK3, and TYK2. It also inhibits Src-family kinases. NS-018 maleate is being developed for the treatment of myeloproliferative neoplasms, including myelofibrosis, polycythemia vera, and essential thrombocythemia. It is not approved for clinical use and is available from research chemical suppliers for preclinical studies.
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| Molecular Formula |
C25H24FN7O4
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| Molecular Weight |
505.5010
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| Exact Mass |
505.187
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| Elemental Analysis |
C, 59.40; H, 4.79; F, 3.76; N, 19.40; O, 12.66
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| CAS # |
1354799-87-3
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| Related CAS # |
Ilginatinib;1239358-86-1;Ilginatinib hydrochloride;1239358-85-0
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| PubChem CID |
56599590
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
37
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| Complexity |
620
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| Defined Atom Stereocenter Count |
1
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| 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
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| InChi Key |
OVAGJAAQMBYZDS-FXSDFHGDSA-N
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| 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
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| 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
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| Synonyms |
NS-018; NS018; NS 018; NS-018 maleate; Ilginatinib maleate;
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ≥ 30 mg/mL (~59.35 mM)
H2O : ~1 mg/mL (~1.98 mM) |
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| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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