| Fragment-based Discovery of New Highly Substituted 1H-Pyrrolo[2,3-b]- and 3H-Imidazolo[4,5-b]-Pyridines as Focal Adhesion Kinase Inhibitors. | |
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MedLine Citation:
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PMID: 23294348 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2013-1-8 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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