Reference Detail

Ref Type

Journal Article

PMID

(22829185)

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	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	1	7	2011 Jul	e29	Blood Cancer J

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Ilginatinib	Ilginatinib	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ilginatinib		NS-018	JAK2 Inhibitor - ATP competitive 15 SRC Inhibitor 31 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
JAK2 V617F	hematologic cancer	sensitive	Ilginatinib	Preclinical	Actionable	In a preclinical study, cells expressing JAK2 V617F were sensitive to treatment with Ilginatinib (NS-018), demonstrating cell growth inhibition and increased apoptotic activity in culture and improved survival in transgenic mouse models (PMID: 22829185).	22829185
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 Ilginatinib (NS-018) in culture (PMID: 22829185).	22829185