Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.
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.
Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA.
A V
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Purandare
T M
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McDevitt
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H
Wan
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You
B
B
Penhallow
X
X
Han
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R
Vuppugalla
Y
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Zhang
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Ruepp
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Trainor
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Lombardo
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Pedicord
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Gottardis
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Ross-Macdonald
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de Silva
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Hosbach
S L
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Emanuel
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Blat
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Fitzpatrick
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Taylor
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McIntyre
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Michaud
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Mulligan
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Lee
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Woolfson
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Lasho
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Pardanani
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Tefferi
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Lorenzi
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C571029:N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide; D047428:Protein Kinase Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2