CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

Tyner, Jeffrey W.; Bumm, Thomas G.P.; Deininger, Jutta; Wood, Lisa J.; Aichberger, Karl J.; Loriaux, Marc; Druker, Brian J.; Burns, Christopher J.; Fantino, Emmanuelle; Deininger, Michael W.

doi:10.1182/blood-2009-05-223727

Cited by 217 publications

(161 citation statements)

References 29 publications

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“…21 The inability of the cells to downregulate JAK2 V617F is also supported by our observations that pJAK2 V617F (Y1007/8) accumulates in the cells for up to 24 h (Figures 2d/e). Consistent with our observation, Tyner et al 22 observed an increased level of pJAK2 (Y1007/8) when treating Ba/F3-JAK2 V617F cells with yet another JAK2 inhibitor and also postulated that this molecule may bind to an open phosphorylated form of JAK2. Hence, the increase of the phosphorylation of Y1007/8 of JAK2 appears to be a class effect induced by adenosine triphosphate-competitive JAK2 inhibitors.…”

Section: Discussionsupporting

confidence: 92%

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SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Hart¹,

Goh²,

et al. 2011

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SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2 V617F -driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/ STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2 V617F patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

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Section: Discussionsupporting

confidence: 92%

“…The weaker antiproliferative activity in HEL92.1.7 compared with other JAK2 V617F mutant cell lines is also reported for other JAK2 inhibitors such as CYT387 (IC 50 ¼ 1.5 mM) 22 and XL019 (IC 50 ¼ 6.8 mM). 24 This suggests that the proliferative signals for these cells may originate from pathways other than JAK2/STAT.…”

Section: Discussionmentioning

confidence: 56%

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Hart¹,

Goh²,

et al. 2011

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“…17,18 Transgenic expression of these mutations into hematopoietic progenitor cells in mice is able to reconstitute many of the features of human MPN including increased red cell mass, splenomegaly and bone marrow fibrosis. 19,20 Collectively, these findings underscore the critical role of aberrant JAK2 signaling in MPNs and highlight JAK2 as an attractive molecular target for the therapeutic intervention in MPN and other malignancies associated with aberrant JAK2-STAT signaling.…”

Section: Introductionmentioning

confidence: 80%

“…30 Transgenic reconstitution of these genetic lesions in mouse bone marrow progenitors recapitulated much of the pathology of human MPN, 19 and pharmacological administration of JAK family inhibitors has been shown to reverse MPN disease features in these animal models. 20,31 Importantly, clinical testing of JAK inhibitors in MPN patients has demonstrated symptomatic relief of the disease, including reductions in spleen size and decreased disease-associated constitutional symptoms. 22 However, it is important to note that these inhibitors currently in clinical testing are generally not selective for JAK2, with several being equipotent to JAK1 and JAK3, which could manifest in deleterious effects on immune cell function.…”

Section: Discussionmentioning

confidence: 99%

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

et al. 2011

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We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

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“…CYT387 is a small molecule ATP-competitive aminopyrimidine derivative with potent JAK kinase inhibitory activity (Pardanani et al, 2009a;Tyner et al, 2010) In the MPN mouse model, CYT387 normalized white cell counts and haematocrit, eliminated splenomegaly, and restored normal levels of pro-inflammatory cytokines (Tyner et al, 2010). Upon cessation of CYT387 the MPN relapsed.…”

Section: Cyt387mentioning

confidence: 99%

Janus kinase Inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?

et al. 2012

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SummaryFollowing the discovery of the Janus kinase (JAK) 2 V617F mutation in 2005 the explosion of research and drug development activity has not only advanced our understanding of the pathogenesis of myeloproliferative neoplasms (MPNs) but also triggered debate about classification, allowed revised diagnostic and response criteria, provided a target for treatment and a mode of monitoring its success. These changes and the resultant clinical research are discussed in this article where we argue that discovery of the JAK2 V617F mutation has signalled the much delayed change in therapeutic paradigm for myelofibrosis and possibly other MPNs from palliation and allowing us to move closer to, but not yet attain, a cure.

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CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

Cited by 217 publications

References 29 publications

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

Janus kinase Inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?

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