Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties
Copyright policy )Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties
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.
- University of Liège Belgium
- Monash University Australia
- University of Tokyo Japan
- KU Leuven Belgium
- Université de Liège (University of Liège) Belgium
Cancer Research, Xenograft Model Antitumor Assay, Fibroblast Growth Factor, Human Umbilical Vein Endothelial Cell, Protein Kinase Inhibitor, Biochimie, biophysique & biologie moléculaire, Small Molecule Libraries, Carcinoma, Lewis Lung, Mice, 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; Cancer Research; Cell Biology; Oncology, HEK293 Cell, Small Molecule Librarie, Allosteric Regulation, Human Umbilical Vein Endothelial Cells, Animals, Humans, Bone Resorption, Phosphorylation, Protein Kinase Inhibitors, 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, Neovascularization, Pathologic, Animal, Pancreatic Neoplasm, Antibodies, Monoclonal, Receptor Protein-Tyrosine Kinases, Cell Biology, Life sciences, Arthritis, Experimental, Receptors, Fibroblast Growth Factor, Xenograft Model Antitumor Assays, Receptor Protein-Tyrosine Kinase, Fibroblast Growth Factors, Pancreatic Neoplasms, HEK293 Cells, Oncology, Sciences du vivant, Biochemistry, biophysics & molecular biology, Human, Signal Transduction
Cancer Research, Xenograft Model Antitumor Assay, Fibroblast Growth Factor, Human Umbilical Vein Endothelial Cell, Protein Kinase Inhibitor, Biochimie, biophysique & biologie moléculaire, Small Molecule Libraries, Carcinoma, Lewis Lung, Mice, 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; Cancer Research; Cell Biology; Oncology, HEK293 Cell, Small Molecule Librarie, Allosteric Regulation, Human Umbilical Vein Endothelial Cells, Animals, Humans, Bone Resorption, Phosphorylation, Protein Kinase Inhibitors, 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, Neovascularization, Pathologic, Animal, Pancreatic Neoplasm, Antibodies, Monoclonal, Receptor Protein-Tyrosine Kinases, Cell Biology, Life sciences, Arthritis, Experimental, Receptors, Fibroblast Growth Factor, Xenograft Model Antitumor Assays, Receptor Protein-Tyrosine Kinase, Fibroblast Growth Factors, Pancreatic Neoplasms, HEK293 Cells, Oncology, Sciences du vivant, Biochemistry, biophysics & molecular biology, Human, Signal Transduction
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).133 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!