title: Fragment-based discovery of focal adhesion kinase inhibitors.
abstract: Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.
authors: Merck KGaA, Merck Serono Research, Darmstadt, Germany. ulrich.graedler@merckgroup.com
authors: Ulrich
authors: U
authors: Grädler
authors: Jörg
authors: J
authors: Bomke
authors: Djordje
authors: D
authors: Musil
authors: Verena
authors: V
authors: Dresing
authors: Martin
authors: M
authors: Lehmann
authors: Günter
authors: G
authors: Hölzemann
authors: Hartmut
authors: H
authors: Greiner
authors: Christina
authors: C
authors: Esdar
authors: Mireille
authors: M
authors: Krier
authors: Timo
authors: T
authors: Heinrich
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D013449:Sulfonamides; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: DFG-out; Focal adhesion kinase; Fragment screening; Surface plasmon resonance; X-ray structure