期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 4, 页码 1662-1672出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901386e
关键词
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资金
- National Institutes of Health [GM032136, AR051448, AR051886, P50-AR054086, YSM0061AM]
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 oil 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 IC50 values of 23 and 50 mu M. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 mu M. 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.
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