428470-19-3Relevant academic research and scientific papers
Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening
Ravindranathan, Krishna P.,Mandiyan, Valsan,Ekkati, Anil R.,Bae, Jae H.,Schlessinger, Joseph,Jorgensen, William L.
supporting information; experimental part, p. 1662 - 1672 (2010/07/04)
Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell, proliferation and differentiation. In search, of inhibitors of FGFRl 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 FGFRl kinase with IC50 values of 23 and 50 μM. Initial optimization of 16 led to the more unsaturated, 40, which has significantly enhanced potency, 1.9 μM., The core structures represent new structural motifs for FGFRl, 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.
