Fragment-Based Discovery of New Highly Substituted 1H-Pyrrolo[2,3-b]- and 3H-Imidazolo[4,5-b]-Pyridines as Focal Adhesion Kinase Inhibitors
详细信息 查看全文
- 作者：Timo Heinrich ; Jeyaprakashnarayanan Seenisamy ; Lourdusamy Emmanuvel ; Santosh S. Kulkarni ; J枚rg Bomke ; Felix Rohdich ; Hartmut Greiner ; Christina Esdar ; Mireille Krier ; Ulrich Gr盲dler ; Djordje Musil
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：1160-1170
- 全文大小：461K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
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.