NS-018

WARNING: This product is for research use only, not for human or veterinary use.

Description:NS-018 is an orally bioavailable, small molecule inhibitor of Janus-associated kinase 2 (JAK2) and Src-family kinases, with potential antineoplastic activity. 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.

Price and Availability

NS-018, purity > 98%, is in stock. Current shipping out time is about 2 weeks after order is received. CoA, QC data and MSDS documents are available in one week after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 205861Name: NS-018CAS#: 1239358-86-1 (free base)Chemical Formula: C21H20FN7Exact Mass: 389.17642Molecular Weight: 389.43Elemental Analysis: C, 64.77; H, 5.18; F, 4.88; N, 25.18

Related CAS #:1239358-86-1 (free base)1239358-85-0 (HCl)1354799-87-3 (maleate)

Synonym:NS018; NS-018; NS 018.

IUPAC/Chemical Name:(S)-N2-(1-(4-fluorophenyl)ethyl)-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine

InChi Key:UQTPDWDAYHAZNT-AWEZNQCLSA-N

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

SMILES Code:CN1N=CC(C2=CC(N[C@H](C3=CC=C(F)C=C3)C)=NC(NC4=NC=CN=C4)=C2)=C1

Technical Data

Additional Information

NS-018  was highly active against JAK2 with a 50% inhibition (IC50) of <1 nM, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 nM), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs. (source: Blood Cancer Journal (2011) 1, e29; doi:10.1038/bcj.2011.29).      

References

1: Rosenthal A, Mesa RA. Janus kinase inhibitors forthe treatment of myeloproliferative neoplasms. Expert Opin Pharmacother. 2014Jun;15(9):1265-76. doi: 10.1517/14656566.2014.913024. Epub 2014 Apr 25. Review. PubMedPMID: 24766055.

2: Kuroda J, Kodama A, Chinen Y, Shimura Y, Mizutani S, Nagoshi H,Kobayashi T, Matsumoto Y, Nakaya Y, Tamura A, Kobayashi Y, Naito H, Taniwaki M.NS-018, a selective JAK2 inhibitor, preferentially inhibits CFU-GM colonyformation by bone marrow mononuclear cells from high-risk myelodysplastic syndromepatients. Leuk Res. 2014 May;38(5):619-24. doi: 10.1016/j.leukres.2014.03.001. Epub2014 Mar 11. PubMed PMID: 24679585.

3: Nakaya Y, Shide K, Naito H, Niwa T, Horio T, Miyake J, Shimoda K.Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model ofmyelofibrosis. Blood Cancer J. 2014 Jan 10;4:e174. doi: 10.1038/bcj.2013.73. PubMedPMID: 24413068; PubMed Central PMCID: PMC3913942.

4: Furqan M, Mukhi N, Lee B, Liu D. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.Biomark Res. 2013 Jan 16;1(1):5. doi: 10.1186/2050-7771-1-5. PubMed PMID:24252238; PubMed Central PMCID: PMC3776247.

5: Tam CS, Verstovsek S. Investigational Janus kinase inhibitors. ExpertOpin Investig Drugs. 2013 Jun;22(6):687-99. doi:10.1517/13543784.2013.774373. Epub 2013 Feb 23. Review. PubMed PMID: 23432430.

6: Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K,Kotera T, Shibayama H, Hori K, Naito H, Shimoda K. Efficacy of NS-018, a potentand selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J. 2011 Jul;1(7):e29. doi: 10.1038/bcj.2011.29. Epub 2011 Jul 22. PubMed PMID: 22829185; PubMedCentral PMCID: PMC3255248.