2. Academic Validation
  3. Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway

Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway

  • J Med Chem. 2011 Jan 13;54(1):262-76. doi: 10.1021/jm1011319.
Stephanos Ioannidis 1,  Michelle L Lamb,  Tao Wang,  Lynsie Almeida,  Michael H Block,  Audrey M Davies,  Bo Peng,  Mei Su,  Hai-Jun Zhang,  Ethan Hoffmann,  Caroline Rivard,  Isabelle Green,  Tina Howard,  Hannah Pollard,  Jon Read,  Marat Alimzhanov,  Geraldine Bebernitz,  Kirsten Bell,  Minwei Ye,  Dennis Huszar,  Michael Zinda
Affiliations

Affiliation

  • 1 Department of Cancer Chemistry, AstraZeneca R&D, Boston, Massachusetts, United States. stephanos.ioannidis@astrazeneca.com
PMID: 21138246 DOI: 10.1021/jm1011319
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.

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