4FYN

Crystal structure of spleen tyrosine kinase complexed with 3-(8-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-phenylamino}-imidazo[1,2-a]pyrazin-5-yl)-phenol

4FYN の概要

• エントリーDOI: 10.2210/pdb4fyn/pdb
• 分子名称: Tyrosine-protein kinase SYK, 3-[8-({4-[ethyl(2-hydroxyethyl)amino]phenyl}amino)imidazo[1,2-a]pyrazin-5-yl]phenol (3 entities in total)
• 機能のキーワード: kinase inhibitor, 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: 34273.45

構造登録者

Kuglstatter, A.,Villasenor, A.G. (登録日: 2012-07-05, 公開日: 2013-01-30, 最終更新日: 2023-09-13)

主引用文献

Lucas, M.C.,Goldstein, D.M.,Hermann, J.C.,Kuglstatter, A.,Liu, W.,Luk, K.C.,Padilla, F.,Slade, M.,Villasenor, A.G.,Wanner, J.,Xie, W.,Zhang, X.,Liao, C.
Rational design of highly selective spleen tyrosine kinase inhibitors.
J.Med.Chem., 55:10414-10423, 2012

PubMed Abstract: A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.

PubMed: 23151054
DOI: 10.1021/jm301367c

実験手法

X-RAY DIFFRACTION (2.318 Å)