6NY4

Crystal structure of JAK3 kinase domain in complex with a pyrrolopyridazine carboxamide inhibitor

6NY4 の概要

• エントリーDOI: 10.2210/pdb6ny4/pdb
• 分子名称: Tyrosine-protein kinase JAK3, 4-{[(2R,3R)-1,3-dihydroxybutan-2-yl]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/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33594.39

構造登録者

Sack, J.S. (登録日: 2019-02-11, 公開日: 2019-05-22, 最終更新日: 2024-03-13)

主引用文献

Spergel, S.H.,Mertzman, M.E.,Kempson, J.,Guo, J.,Stachura, S.,Haque, L.,Lippy, J.S.,Zhang, R.F.,Galella, M.,Pitt, S.,Shen, G.,Fura, A.,Gillooly, K.,McIntyre, K.W.,Tang, V.,Tokarski, J.,Sack, J.S.,Khan, J.,Carter, P.H.,Barrish, J.C.,Nadler, S.G.,Salter-Cid, L.M.,Schieven, G.L.,Wrobleski, S.T.,Pitts, W.J.
Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.
Acs Med.Chem.Lett., 10:306-311, 2019

PubMed Abstract: The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib , has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

PubMed: 30891131
DOI: 10.1021/acsmedchemlett.8b00508

実験手法

X-RAY DIFFRACTION (2.33 Å)