4GU9

Focal adhesion kinase catalytic domain in complex with (2-Fluoro-phenyl)-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine

Summary for 4GU9

• Entry DOI: 10.2210/pdb4gu9/pdb
• Descriptor: Focal adhesion kinase 1, N-(2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: protein tyrosine kinase, transferase, atp binding
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction, focal adhesion: Q05397
• Total number of polymer chains: 2
• Total formula weight: 64374.28

Authors

Musil, D. (deposition date: 2012-08-29, release date: 2013-09-04, Last modification date: 2024-10-16)

Primary citation

Heinrich, T.,Seenisamy, J.,Emmanuvel, L.,Kulkarni, S.S.,Bomke, J.,Rohdich, F.,Greiner, H.,Esdar, C.,Krier, M.,Gradler, U.,Musil, D.
Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.
J.Med.Chem., 56:1160-1170, 2013

PubMed Abstract: 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.

PubMed: 23294348
DOI: 10.1021/jm3016014

Experimental method

X-RAY DIFFRACTION (2.4 Å)