8QQY
Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with JG165
Summary for 8QQY
| Entry DOI | 10.2210/pdb8qqy/pdb |
| Descriptor | 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) |
| Functional Keywords | epha2, ephrin type-a receptor 2, inhibitor, macrocycle, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35699.19 |
| Authors | Zhubi, R.,Gerninghaus, J.,Knapp, S.,Kraemer, A.,Structural Genomics Consortium (SGC) (deposition date: 2023-10-06, release date: 2023-11-22, Last modification date: 2024-11-27) |
| Primary citation | 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 Cited by 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: 39028937DOI: 10.1021/acs.jmedchem.4c00411 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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