title: Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.
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.
authors.affiliation: Merck Serono Research, Merck KGaA , 64271 Darmstadt, Germany. timo.heinrich@merckgroup.com
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.forename: Jeyaprakashnarayanan
authors.initials: J
authors.lastname: Seenisamy
authors.forename: Lourdusamy
authors.initials: L
authors.lastname: Emmanuvel
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Kulkarni
authors.forename: Jörg
authors.initials: J
authors.lastname: Bomke
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.forename: Hartmut
authors.initials: H
authors.lastname: Greiner
authors.forename: Christina
authors.initials: C
authors.lastname: Esdar
authors.forename: Mireille
authors.initials: M
authors.lastname: Krier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
mesh_terms: D002851:Chromatography, High Pressure Liquid; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011725:Pyridines; D051416:Focal Adhesion Protein-Tyrosine Kinases