ABSTRACT
Recepteur d'Origine Nantais known as RON is a member of the receptor tyrosine kinase (RTK) superfamily which has recently gained increasing attention as cancer target for therapeutic intervention. The aim of this work was to perform an alignment-independent three-dimensional quantitative structure-activity relationship (3D QSAR) study for a series of RON inhibitors. A 3D QSAR model based on GRid-INdependent Descriptors (GRIND) methodology was generated using a set of 19 compounds with RON inhibitory activities. The generated 3D QSAR model revealed the main structural features important in the potency of RON inhibitors. The results obtained from the presented study can be used in lead optimization projects for designing of novel compounds where inhibition of RON is needed.
Subject(s)
Quantitative Structure-Activity Relationship , Receptor Protein-Tyrosine Kinases , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
BACKGROUND: RON (Recepteur d'Origine Nantais) receptor tyrosine kinase is a promising target for anti-cancer therapeutics. The aim of this study was to identify new RON inhibitors using virtual screening methods. METHODS: To this end, a ligand-based virtual screening approach was employed for screening of ZINC database on the homology model of RON receptor. All the selected hits were inspected in terms of drug-likeness, ADME properties, and toxicity profiles. Ligand-based similarity searches along with further filtering criteria led to the identification of two compounds, TKI1 and TKI2 that were evaluated using inâ vitro cell-based RON inhibition assays. RESULTS: The results showed that TKI1 and TKI2 could reduce phosphorylation of RON. Both compounds showed inhibitory activity of the downstream mTOR pathway with no apparent effects on other signaling mediators in a dose-dependent manner. CONCLUSION: These compounds can provide a basis for developing novel anti-RON inhibitors applicable to cancer therapy using medicinal chemistry-oriented optimization strategies.
Subject(s)
Receptor Protein-Tyrosine Kinases , Signal Transduction , LigandsABSTRACT
New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained.
Subject(s)
Drug Design , Heterocyclic Compounds, 2-Ring/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrazoles/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor/drug effects , Chemistry Techniques, Synthetic , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Lactams/chemistry , Molecular Docking Simulation , Molecular Targeted Therapy , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathologyABSTRACT
New carboxamide head group analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent and selective inhibitors of RON enzyme versus c-Met RTK were obtained.
Subject(s)
Drug Design , Heterocyclic Compounds, 2-Ring/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemistry , Binding Sites , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Pyrazoles/chemistry , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.
