4HGE

JAK2 kinase (JH1 domain) in complex with compound 8

Summary for 4HGE

• Entry DOI: 10.2210/pdb4hge/pdb
• Descriptor: Tyrosine-protein kinase JAK2, N-[1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3 entities in total)
• Functional Keywords: protein kinase, phosphotransfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• Total number of polymer chains: 2
• Total formula weight: 71389.81

Authors

Eigenbrot, C.,Ultsch, M. (deposition date: 2012-10-08, release date: 2012-10-24, Last modification date: 2024-11-20)

Primary citation

Hanan, E.J.,van Abbema, A.,Barrett, K.,Blair, W.S.,Blaney, J.,Chang, C.,Eigenbrot, C.,Flynn, S.,Gibbons, P.,Hurley, C.A.,Kenny, J.R.,Kulagowski, J.,Lee, L.,Magnuson, S.R.,Morris, C.,Murray, J.,Pastor, R.M.,Rawson, T.,Siu, M.,Ultsch, M.,Zhou, A.,Sampath, D.,Lyssikatos, J.P.
Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
J.Med.Chem., 55:10090-10107, 2012

PubMed Abstract: The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

PubMed: 23061660
DOI: 10.1021/jm3012239

Experimental method

X-RAY DIFFRACTION (2.3 Å)