PDB 4GU9 deposited: 2012-08-29 modified: 2013-09-04
Title Focal adhesion kinase catalytic domain in complex with (2-Fluoro-phenyl)-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine
Authors Bomke, J., Emmanuvel, L., Esdar, C., Gradler, U., Greiner, H., Heinrich, T., Krier, M., Kulkarni, S.S., Musil, D., Rohdich, F., Seenisamy, J.
Structure factors resolution 2.4 rfactor 0.1779 rfree 0.2208
DPI 0.61 theoretical min: 0.28
Related PDB Entries 4GU6

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
4GU9/1 4GU9 1 monomer 0 1 1 1868
4GU9/2 4GU9 2 monomer 0 1 1 1916