Abstract
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
MeSH terms
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Animals
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Cell Line, Tumor
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Crystallography, X-Ray
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Dogs
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Female
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Humans
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In Vitro Techniques
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / chemistry
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Models, Molecular
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Phosphorylation
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Protein Conformation
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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STAT Transcription Factors / metabolism
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STAT Transcription Factors / physiology*
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / metabolism
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Signal Transduction
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Stereoisomerism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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AZD 1480
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Pyrazoles
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Pyrimidines
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STAT Transcription Factors
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Janus Kinase 2