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|Ref Type||Journal Article|
|Authors||Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K, Kotera T, Shibayama H, Hori K, Naito H, Shimoda K|
|Title||Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms.|
|Journal||Blood cancer journal|
|Abstract Text||Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1 n, 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; IC(50)=11-120 n), 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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Ilginatinib||NS-018||JAK2 Inhibitor - ATP competitive 14 SRC Inhibitor 30 YES Inhibitor 3||Ilginatinib (NS-018) inhibits JAK2, including JAK2 V617F, as well as SRC family members, including SRC, FYN, and YES, potentially leading to decreased cell proliferation (PMID: 24413068, PMID: 22829185, PMID: 29941953).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|JAK3 A572V||acute myeloid leukemia||predicted - resistant||Ilginatinib||Preclinical - Cell culture||Actionable||In a preclinical study, an acute myeloid leukemia cell line harboring JAK3 A572V was insensitive to treatment with NS-108 in culture (PMID: 22829185).||22829185|
|JAK2 V617F||hematologic cancer||sensitive||Ilginatinib||Preclinical||Actionable||In a preclinical study, cells expressing JAK2 V617F were sensitive to treatment with NS-108, demonstrating cell growth inhibition and increased apoptotic activity in culture and improved survival in transgenic mouse models (PMID: 22829185).||22829185|