Summary
PDB 4GU6 deposited: 2012-08-29 modified: 2013-09-04
Title FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-{3-[(5-Cyano-2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)- methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide
Authors Bomke, J., Emmanuvel, L., Esdar, C., Gradler, U., Greiner, H., Heinrich, T., Krier, M., Kulkarni, S.S., Musil, D., Rohdich, F., Seenisamy, J.
Method X-RAY DIFFRACTION
Structure factors resolution 1.95 rfactor 0.1695 rfree 0.1944
DPI 0.33 theoretical min: 0.15
Related PDB Entries 4GU9
Citations

Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.

J.Med.Chem. 2013 Feb; 56(3):1160-1170 doi:10.1021/jm3016014

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2311330
PubMed 23294348 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4GU6/1 4GU6 1 dimer 0 2 2 4234
4GU6/2 4GU6 2 monomer 0 1 1 2236
4GU6/3 4GU6 3 monomer 0 1 1 1998