6B5J

TNNI3K complexed with a 4,6-diaminopyrimidine

6B5J の概要

• エントリーDOI: 10.2210/pdb6b5j/pdb
• 分子名称: Serine/threonine-protein kinase TNNI3K, N-methyl-3-[(6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)amino]benzene-1-sulfonamide (3 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q59H18
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 141247.10

構造登録者

Shewchuk, L.M.,Philp, J. (登録日: 2017-09-29, 公開日: 2018-04-04, 最終更新日: 2024-03-13)

主引用文献

Philp, J.,Lawhorn, B.G.,Graves, A.P.,Shewchuk, L.,Rivera, K.L.,Jolivette, L.J.,Holt, D.A.,Gatto, G.J.,Kallander, L.S.
4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors.
J. Med. Chem., 61:3076-3088, 2018

PubMed Abstract: Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.

PubMed: 29561151
DOI: 10.1021/acs.jmedchem.8b00125

実験手法

X-RAY DIFFRACTION (2.97 Å)