5TIU

Crystal structure of SYK kinase domain with inhibitor

5TIU の概要

• エントリーDOI: 10.2210/pdb5tiu/pdb
• 分子名称: Tyrosine-protein kinase SYK, 5-{[(2S)-2-aminopropyl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide (3 entities in total)
• 機能のキーワード: carboxamide spleen tyrosine kinase (syk), transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane : P43405
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34194.36

構造登録者

Ellis, J.M.,Altman, M.D.,Cash, B.,Haidle, A.M.,Kubiak, R.L.,Maddess, M.L.,Yan, Y.,Northrup, A.B. (登録日: 2016-10-03, 公開日: 2017-01-11, 最終更新日: 2024-04-03)

主引用文献

Ellis, J.M.,Altman, M.D.,Cash, B.,Haidle, A.M.,Kubiak, R.L.,Maddess, M.L.,Yan, Y.,Northrup, A.B.
Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.
ACS Med Chem Lett, 7:1151-1155, 2016

PubMed Abstract: Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a strain.

PubMed: 27994755
DOI: 10.1021/acsmedchemlett.6b00353

実験手法

X-RAY DIFFRACTION (1.49 Å)