4GK4

Human EphA3 Kinase domain in complex with ligand 90

Summary for 4GK4

• Entry DOI: 10.2210/pdb4gk4/pdb
• Related: 4GK2 4GK3
• Descriptor: EPH receptor A3, 8-butyl-1-methyl-7-(5-methyl-1H-indazol-4-yl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, atp-binding, phosphorylation, membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40849.61

Authors

Dong, J.,Caflisch, A. (deposition date: 2012-08-10, release date: 2013-01-23, Last modification date: 2023-11-08)

Primary citation

Lafleur, K.,Dong, J.,Huang, D.,Caflisch, A.,Nevado, C.
Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography.
J.Med.Chem., 56:84-96, 2013

PubMed Abstract: Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.

PubMed: 23253074
DOI: 10.1021/jm301187e

Experimental method

X-RAY DIFFRACTION (2.1 Å)