4HGE

JAK2 kinase (JH1 domain) in complex with compound 8

4HGE の概要

• エントリーDOI: 10.2210/pdb4hge/pdb
• 分子名称: 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)
• 機能のキーワード: protein kinase, phosphotransfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71389.81

構造登録者

Eigenbrot, C.,Ultsch, M. (登録日: 2012-10-08, 公開日: 2012-10-24, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)