Document Detail

Fragment-based Discovery of New Highly Substituted 1H-Pyrrolo[2,3-b]- and 3H-Imidazolo[4,5-b]-Pyridines as Focal Adhesion Kinase Inhibitors.
MedLine Citation:
PMID:  23294348     Owner:  NLM     Status:  Publisher    
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 derivatisations provided compounds with sub-micromolar 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.
Timo Heinrich; Jeyaprakashnarayanan Seenisamy; Lourdusamy Emmanuvel; Santosh S Kulkarni; Jörg Bomke; Felix Rohdich; Hartmut Greiner; Christina Esdar; Mireille Krier; Ulrich Grädler; Djordje Musil
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-8
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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