5VO6

CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN IN COMPLEX WITH A PYRROLOPYRIDAZINE INHIBITOR

5VO6 の概要

• エントリーDOI: 10.2210/pdb5vo6/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 4-{[(1R,3S)-3-amino-2,2,3-trimethylcyclopentyl]amino}-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (3 entities in total)
• 機能のキーワード: transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : P52333
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33631.50

構造登録者

Sack, J.S. (登録日: 2017-05-02, 公開日: 2017-05-31, 最終更新日: 2024-03-13)

主引用文献

Hynes, J.,Wu, H.,Kempson, J.,Duan, J.J.,Lu, Z.,Jiang, B.,Stachura, S.,Tokarski, J.S.,Sack, J.S.,Khan, J.A.,Lippy, J.S.,Zhang, R.F.,Pitt, S.,Shen, G.,Gillooly, K.,McIntyre, K.,Carter, P.H.,Barrish, J.C.,Nadler, S.G.,Salter-Cid, L.M.,Fura, A.,Schieven, G.L.,Pitts, W.J.,Wrobleski, S.T.
Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
Bioorg. Med. Chem. Lett., 27:3101-3106, 2017

PubMed Abstract: A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

PubMed: 28539220
DOI: 10.1016/j.bmcl.2017.05.043

実験手法

X-RAY DIFFRACTION (2.65 Å)