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Ilginatinib (NS018; NS-018) HCl, the hydrochloride salt form of NS-018, is an oral and potent JAK2 inhibitor with potential anticancer 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.
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| ln Vitro |
An very potent JAK2 inhibitor, ilginatinib hydrochloride (NS-018 hydrochloride) with an IC50 of 0.72 nM and a 46-, 54-, and 31-fold selectivity for JAK2 over JAK1 (IC50, 33 nM), JAK3 (IC50, 39 nM), and Tyk2 (IC50, 22 nM). Additionally, ilginatinib hydrochloride mildly inhibits ABL and FLT3, with 45- and 90-fold selectivity for JAK2, and inhibits Src-family kinases, particularly SRC and FYN. At an IC50 of 11–120 nM, iligatinib hydrochloride exhibits strong inhibitory activity against cell lines with mutations in JAK2V617F or MPLW515L, as well as the TEL-JAK2 fusion gene, which expresses a constitutively activated JAK2. However, it is only slightly cytotoxic against the majority of other hematopoietic cell lines that lack constitutively activated JAK2[1]. The generation of colony-forming units, granulocyte/macrophages (CFU-GM) from bone marrow mononuclear cells (BMMNCs) derived from myelodysplastic syndrome (MDS) is preferentially suppressed by ilginatinib hydrochloride (0.5 μM). In CFU-GM-forming cells from MDS patients, ilginatinib hydrochloride (1 μM) decreases the phosphorylation of STAT3, the downstream kinase of JAK2[2].
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In a mouse Ba/F3-JAK2V617F illness model, iligatinib hydrochloride (NS-018 hydrochloride) (12.5, 25, 50, 100 mg/kg, po) potently prolongs mouse survival and lowers splenomegaly[1]. In JAK2V617F transgenic mice, ilginatinib hydrochloride (25, 50 mg/kg, po) prolongs longevity, improves nutritional status, and dramatically lowers leukocytosis, hepatosplenomegaly, and extramedullary hematopoiesis[1].
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| References |
[1]. Nakaya Y, et al. 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]. Kuroda J, et al. 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 |
| Molecular Formula |
C21H21CLFN7
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|---|---|
| Molecular Weight |
425.889745473862
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| CAS # |
1239358-85-0
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| Related CAS # |
Ilginatinib maleate;1354799-87-3;Ilginatinib;1239358-86-1
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| SMILES |
[H]Cl.CN1N=CC(C2=CC(N[C@H](C3=CC=C(F)C=C3)C)=NC(NC4=NC=CN=C4)=C2)=C1
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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 : ≥ 35 mg/mL (~82.18 mM)
H2O : ~2 mg/mL (~4.70 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.87 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 | 2.3480 mL | 11.7401 mL | 23.4802 mL | |
| 5 mM | 0.4696 mL | 2.3480 mL | 4.6960 mL | |
| 10 mM | 0.2348 mL | 1.1740 mL | 2.3480 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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