ABSTRACT
RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.
ABSTRACT
Fibroblast growth factor receptors (FGFRs) and associated ligands (FGFs) are a family of well-validated targets for therapeutic interventions notably in cancer diseases in relation to their prominent roles in cell growth, survival, differentiation and angiogenesis. This patent review encompasses all different approaches (modulators of FGF or FGFR expression, anti-FGF antibodies, anti-FGFR antibodies, FGF traps, tyrosine-kinase (TK) inhibitors, allosteric modulators) used to block completely or partially the activities of the FGF-FGFR complexes resulting in clinical drug candidates or tool agents. Comparative analysis of biochemical, pharmacological or clinical data will be discussed for each class of molecules together with some perspectives.
Subject(s)
Fibroblast Growth Factors , Neoplasms/drug therapy , Receptors, Fibroblast Growth Factor , Animals , Antibodies/therapeutic use , Antineoplastic Agents/therapeutic use , Aptamers, Nucleotide/therapeutic use , Fibroblast Growth Factors/immunology , Fibroblast Growth Factors/metabolism , Humans , Patents as Topic , Peptides/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/immunology , Receptors, Fibroblast Growth Factor/metabolismSubject(s)
Protein Kinase Inhibitors/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Allosteric Regulation/drug effects , Allosteric Site/drug effects , Extracellular Space/drug effects , Humans , Protein Binding , Protein Conformation/drug effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Small Molecule Libraries/pharmacology , Allosteric Regulation , Animals , Antibodies, Monoclonal/pharmacology , Arthritis, Experimental/drug therapy , Bone Resorption/drug therapy , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Fibroblast Growth Factors/antagonists & inhibitors , Fibroblast Growth Factors/metabolism , HEK293 Cells , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Neovascularization, Pathologic/drug therapy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.
