Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, PROTEIN-COUPLED RECEPTORS, FIBROBLAST, MODULATION, BINDING, VEGF, METASTASIS, THERAPY, DISEASE, CANCER, CELLS, Allosteric Regulation, Animals, Antibodies, Monoclonal, Arthritis, Experimental, Bone Resorption, Carcinoma, Lewis Lung, Fibroblast Growth Factors, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Mice, Neovascularization, Pathologic, Pancreatic Neoplasms, Phosphorylation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Receptors, Fibroblast Growth Factor, Signal Transduction, Small Molecule Libraries, Xenograft Model Antitumor Assays, Oncology & Carcinogenesis, 1109 Neurosciences, 1112 Oncology and Carcinogenesis
Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.