8QQY

Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with JG165

8QQY の概要

• エントリーDOI: 10.2210/pdb8qqy/pdb
• 分子名称: Ephrin type-A receptor 2, 6-(4-fluoranyl-3-methoxy-phenyl)-13$l^{6}-thia-2,4,8,12,19-pentazatricyclo[12.3.1.1^{3,7}]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: epha2, ephrin type-a receptor 2, inhibitor, macrocycle, structural genomics, structural genomics consortium, sgc, transferase
• 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: 35699.19

構造登録者

Zhubi, R.,Gerninghaus, J.,Knapp, S.,Kraemer, A.,Structural Genomics Consortium (SGC) (登録日: 2023-10-06, 公開日: 2023-11-22, 最終更新日: 2024-11-27)

主引用文献

Gerninghaus, J.,Zhubi, R.,Kramer, A.,Karim, M.,Tran, D.H.N.,Joerger, A.C.,Schreiber, C.,Berger, L.M.,Berger, B.T.,Ehret, T.A.L.,Elson, L.,Lenz, C.,Saxena, K.,Muller, S.,Einav, S.,Knapp, S.,Hanke, T.
Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors.
J.Med.Chem., 67:12534-12552, 2024

PubMed Abstract: Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, , we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle provided a basis for further optimization by specifically targeting the back pocket, resulting in compound , a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.

PubMed: 39028937
DOI: 10.1021/acs.jmedchem.4c00411

実験手法

X-RAY DIFFRACTION (1.8 Å)