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

• Published in: Molecular informatics Vol. 41; no. 1; pp. e2000181 - n/a
• Main Authors: Zarei, Omid, Faham, Najme, Vankayalapati, Hariprasad, Raeppel, Stéphane L., Welm, Alana L., Hamzeh‐Mivehroud, Maryam
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2022
• Subjects: Cancer; Homology; Inhibitors; Kinases; Ligands; Optimization; Phosphorylation; Protein-tyrosine kinase receptors; Receptor Protein-Tyrosine Kinases; receptor tyrosine kinase; Receptors; RON; Ron protein; Screening; Signal Transduction; TOR protein; Toxicity; Tyrosine; virtual screening; RON; receptor tyrosine kinase; virtual screening; Cancer
• ISSN: 1868-1743; 1868-1751
• DOI: 10.1002/minf.202000181

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.