title: Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.
abstract: Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC(50) values of 23 and 50 microM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 microM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Ravindranathan
authors.forename: Valsan
authors.initials: V
authors.lastname: Mandiyan
authors.forename: Anil R
authors.initials: AR
authors.lastname: Ekkati
authors.forename: Jae H
authors.initials: JH
authors.lastname: Bae
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D016208:Databases, Factual; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D046609:Libraries, Digital; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051496:Receptor, Fibroblast Growth Factor, Type 1