2XA4

Inhibitors of Jak2 Kinase domain

Summary for 2XA4

• Entry DOI: 10.2210/pdb2xa4/pdb
• Related: 2B7A 2W1I
• Descriptor: TYROSINE-PROTEIN KINASE JAK2, 5-CHLORO-N2-[(1S)-1-(5-FLUOROPYRIMIDIN-2-YL)ETHYL]-N4-(5-METHYL-1H-PYRAZOL-3-YL)PYRIMIDINE-2,4-DIAMINE (3 entities in total)
• Functional Keywords: kinase, membrane, transferase, atp-binding, proto-oncogene, phosphoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70861.11

Authors

Read, J.,Green, I.,Pollard, H.,Howard, T.,Mott, R. (deposition date: 2010-03-26, release date: 2010-12-15, Last modification date: 2024-11-06)

Primary citation

Ioannidis, S.,Lamb, M.L.,Wang, T.,Almeida, L.,Block, M.H.,Davies, A.M.,Peng, B.,Su, M.,Zhang, H.,Hoffmann, E.,Rivard, C.,Green, I.,Howard, T.,Pollard, H.,Read, J.,Alimzhanov, M.,Bebernitz, G.,Bell, K.,Ye, M.,Huszar, D.,Zinda, M.
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., 54:262-, 2011

PubMed 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.

PubMed: 21138246
DOI: 10.1021/JM1011319

Experimental method

X-RAY DIFFRACTION (2.04 Å)