An alignment-independent three-dimensional quantitative structure-activity relationship study on ron receptor tyrosine kinase inhibitors.

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.

Ligand-based Discovery of Novel Small Molecule Inhibitors of RON Receptor Tyrosine Kinase.

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 in 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.

Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004.

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.

Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors.

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.

Design and synthesis of close analogs of LCRF-0004, a potent and selective RON receptor tyrosine kinase inhibitor.

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.

Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors.

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.