| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| Targets |
IC50 for JAK2:0.72 nM; Tyk2:22 nM; JAK1:33 nM; JAK3:39 nM
The primary target of Ilginatinib 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. Ilginatinib acts as a 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 kinases, including JAK1 (IC50 = 33 nM), JAK3 (IC50 = 39 nM), and TYK2 (IC50 = 22 nM). In addition to JAK2, Ilginatinib inhibits Src-family tyrosine 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, addressing a significant unmet need in the approximately 30% of myelofibrosis patients with severe thrombocytopenia. |
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| ln Vitro |
Ilginatinib (NS-018) is a very potent JAK2 inhibitor, showing 46, 54, and 31-fold selectivity for JAK2 over JAK1 (IC50, 33 nM), JAK3 (IC50, 39 nM), and Tyk2 (IC50, 22 nM). Its IC50 is 0.72 nM. Along with mildly inhibiting ABL and FLT3 with 45- and 90-fold selectivity for JAK2, ignitinib (NS-018) also inhibits Src-family kinases, namely SRC and FYN. When it comes to cell lines with mutations in JAK2V617F or MPLW515L, or the TEL-JAK2 fusion gene that expresses a constitutively activated JAK2, NS-018 exhibits potent inhibitory activity with an IC50 of 11-120 nM. However, its cytotoxicity against the majority of other hematopoietic cell lines that lack constitutively activated JAK2 is minimal[1]. When obtained from bone marrow mononuclear cells (BMMNCs) of patients with myelodysplastic syndrome (MDS), ilginatinib (NS-018) (0.5 μM) preferentially reduces the development of colony-forming units, granulocyte/macrophages (CFU-GM). MDS patients' CFU-GM-forming cells show suppression of the phosphorylation of STAT3, the downstream kinase of JAK2, when exposed to ignitinib (NS-018) at a concentration of 1 μM.
In vitro, Ilginatinib is highly active against JAK2 with an IC50 of <1 nM. It shows potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene), with IC50 values of 11-120 nM. The compound shows only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2, indicating a favorable selectivity profile. Ilginatinib preferentially suppresses in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients, confirming its activity against patient-derived hematopoietic progenitors. The compound's inhibition of Src-family kinases may contribute to its anti-proliferative and anti-metastatic effects, as Src kinases are involved in cell migration, invasion, and angiogenesis. |
| ln Vivo |
In a mouse Ba/F3-JAK2V617F illness model, ilginatinib (NS-018) (12.5, 25, 50, 100 mg/kg, po) potently prolongs animal survival and decreases splenomegaly[1]. In JAK2V617F transgenic mice, ilginatinib (NS-018) (25, 50 mg/kg, po) dramatically lowers leukocytosis, hepatosplenomegaly, and extramedullary hematopoiesis, enhances nutritional status, and increases survival time.
In vivo, Ilginatinib 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, Ilginatinib significantly reduces leukocytosis, hepatosplenomegaly, and extramedullary hematopoiesis, improves nutritional status, and prolongs survival. These findings suggest that Ilginatinib will be a promising candidate for the treatment of MPNs. 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 Ilginatinib 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 Ilginatinib is a potent and selective JAK2 inhibitor with activity against Src-family kinases. Binding assays using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be employed to measure the affinity of Ilginatinib for JAK2 and to confirm its ATP-competitive mechanism of action.
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| Cell Assay |
>Bone marrow mononuclear cells (BMMNCs) from healthy volunteers and myelodysplastic syndrome (MDS) patients are incubated in MethoCult GF H4434 methylcellulose medium containing various hematopoietic cytokines at 1.0 × 105 cells/mL with or without NS-018 at 37°C in a humidified atmosphere of 5% CO2. Commercially available purified normal human CD34-positive (CD34+) BM cells are used as a control. Burst-forming unit-erythroid (BFU-E) and colonyforming unit-granulocyte/macrophage (CFU-GM) colonies are counted under an inverted microscope on day 14 of culture[2]. |
| Animal Protocol |
>Mice[1] Female BALB/c nude mice are placed in blanket cages in an environment maintained at 21-25°C and 45-65% relative humidity, with artificial illumination for 12 h and a ventilation frequency of at least 15 times/h. They are allowed free access to food pellets and tap water. Ba/F3-JAK2V617F cells (106 per mouse) are inoculated intravenously into 7-week-old mice. Administration of vehicle (0.5% methylcellulose) or NS-018 twice daily by oral gavage begins the day after cell inoculation. Survival is monitored daily, and moribund mice are humanely killed and their time of death is recorded for purposes of survival analysis. In a parallel study, all mice are humanely killed after 8 days of administration, and their spleens are removed and weighed[1]. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Ilginatinib indicate that it has a molecular weight of 389.43 and a molecular formula of C21H20FN7. The compound is orally bioavailable, enabling convenient administration for in vivo studies. It is soluble in DMSO at a concentration of 34 mg/mL (87.31 mM). For storage, the powder should be kept at -20°C for up to 3 years, and stock solutions should be stored at -80°C for up to 2 years. The compound's physicochemical properties suggest that it has favorable drug-like characteristics for oral administration.
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| Toxicity/Toxicokinetics |
The toxicological profile of Ilginatinib 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, Ilginatinib'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, Ilginatinib 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 has been used in clinical trials investigating the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Iginatinib is a small molecule inhibitor with high oral bioavailability that inhibits Janus kinase 2 (JAK2) and Src family kinases, possessing potential antitumor activity. Iginatinib competitively binds to JAK2 and its mutant JAK2V617F with ATP, thereby inhibiting the activation of JAK2 and its downstream molecules in the JAK2/STAT3 (signal transduction and activator of transcription 3) signaling pathway. This pathway plays a crucial role in normal development, particularly in hematopoiesis. Furthermore, iginatinib also inhibits Src family tyrosine kinases. Ultimately, this leads to tumor cell apoptosis. JAK2 is the most common mutated gene in bcr-abl negative myeloproliferative disorders (MPD); JAK2V617F is a constitutively activated kinase that can activate the JAK/STAT signaling pathway and disrupt cell growth and function. Its expression can convert hematopoietic cells into cytokine-independent growth.
Ilginatinib (NS-018) is a highly active, orally bioavailable JAK2 inhibitor with potential antineoplastic activity. It is also known as NS-018. 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. Ilginatinib shows potent antiproliferative activity against cell lines expressing constitutively activated JAK2 and is being developed for the treatment of myeloproliferative neoplasms. It is not approved for clinical use and is available from research chemical suppliers for preclinical studies. |
| Molecular Formula |
C21H20FN7
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|---|---|
| Molecular Weight |
389.4288
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| Exact Mass |
389.176
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| CAS # |
1239358-86-1
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| Related CAS # |
Ilginatinib maleate;1354799-87-3;Ilginatinib hydrochloride;1239358-85-0
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| PubChem CID |
46866319
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
586.8±60.0 °C at 760 mmHg
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| Flash Point |
308.7±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.671
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| LogP |
2.66
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
501
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H](C1=CC=C(C=C1)F)NC2=CC(=CC(=N2)NC3=NC=CN=C3)C4=CN(N=C4)C
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| InChi Key |
UQTPDWDAYHAZNT-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C21H20FN7/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/h3-14H,1-2H3,(H2,24,26,27,28)/t14-/m0/s1
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| Chemical Name |
6-N-[(1S)-1-(4-fluorophenyl)ethyl]-4-(1-methylpyrazol-4-yl)-2-N-pyrazin-2-ylpyridine-2,6-diamine
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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 |
| 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 : ~100 mg/mL (~256.79 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.42 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 (6.42 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5679 mL | 12.8393 mL | 25.6786 mL | |
| 5 mM | 0.5136 mL | 2.5679 mL | 5.1357 mL | |
| 10 mM | 0.2568 mL | 1.2839 mL | 2.5679 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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