Kinase drug discovery approaches in chronic myeloproliferative disorders

Kumar, Chandan; Purandare, Ashok V.; Lee, F Y; Lorenzi, Matthew V.

doi:10.1038/onc.2009.107

Cited by 30 publications

(17 citation statements)

References 79 publications

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“…Targeting JAK2 has emerged as an attractive strategy of novel drug development because it is mutated in many patients with myeloproliferative disorders [31,37]. Most of the JAK2-directed drug discovery efforts are in early/ mid-stage of clinical development or are yet to reach the clinic.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the JAK2-directed drug discovery efforts are in early/ mid-stage of clinical development or are yet to reach the clinic. Of these small molecule inhibitors, lestaurtinib and INCB-18424 are currently being evaluated in phase II clinical trials [37]. Thus, it will be very interesting to evaluate the effectiveness of these molecules in the treatment of gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

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MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

et al. 2010

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“…21 The compounds in development inhibit JAK2 tyrosine kinase activity by competing for ATP binding and have varying degrees of cross inhibitory activity to other JAK family members, such as JAK1 and JAK3, as well as other kinases in the kinome. 22 A consequence of non-selectivity to JAK1 or JAK3 is thought to be a potential for immunosuppression given the role of these kinases in immune cell function 23 and as such, compounds with such activities may be associated with additional dose-limiting toxicities compared with other JAK2-selective inhibitors.…”

Section: Introductionmentioning

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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“…Most of the drug discovery efforts on the identification of kinase inhibitors have been focused on ATPmimetic small molecule inhibitors. 22 Given that JAK2 is a tyrosine kinase, the discovery of activating mutations naturally resulted in a great deal of excitement and optimism in identifying and developing JAK2 inhibitors for the treatment of MPNs. 23 JAK2V617F-mutated enzyme is often compared to the BCR-ABL oncoprotein from the standpoint of drug development.…”

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Therapeutic Potential of JAK2 Inhibitors

Verstovšek

2013

The Journal of OncoPathology

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The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.Virtually every intracellular signal transduction pathway is wired through a phosphotransfer cascade mediated by kinases. 1 Humans express more than 500 kinases that phosphorylate distinct proteins, typically on the tyrosine, serine or threonine residues. Janus-associated kinase 2 (JAK2) is one member of a family of four cytoplasmic tyrosine kinases that also includes JAK1, JAK3 and Tyk2. 2 The JAK enzymes are required for signaling by cytokine and growth factor receptors that lack intrinsic kinase activity. 3,4 There appear to be some overlapping roles for JAK family members, as most signaling pathways involve more than one JAK, with the exception of some growth factors such as erythropoietin and thrombopoietin, which only utilize JAK2. JAK1 plays a major role in mediating the signaling of a number of proinflammatory cytokines, often in association with other JAK Aberrant signal transduction by a tyrosine kinase can be leukemogenic, and several lines of evidence support the conclusion that JAK/STAT signaling is exaggerated in hematological malignancies and likely contributes to disease pathogenesis. 3,[5][6][7] These include, for example a) the demonstrated ability of JAK/STAT to increase the transcription of genes such as cMyc, cyclin D, Mcl-1, and Bcl-XL that affect growth, proli...

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Kinase drug discovery approaches in chronic myeloproliferative disorders

Cited by 30 publications

References 79 publications

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

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

Therapeutic Potential of JAK2 Inhibitors

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