Omid Zarei1, Najme Faham2,3, Hariprasad Vankayalapati2,4, Stéphane L Raeppel5, Alana L Welm2,3, Maryam Hamzeh-Mivehroud6,7. 1. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran. 2. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 3. Department of Oncological Sciences, University of Utah, Salt Lake City, Utah. 4. College of Pharmacy, University of Utah, Salt Lake City, Utah. 5. ChemRF Laboratories, 3194, rue Claude-Jodoin, Montréal, QC, H1Y 3M2, Canada. 6. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 7. School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract
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.
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.
Authors: Maiia E Bragina; Antoine Daina; Marta A S Perez; Olivier Michielin; Vincent Zoete Journal: Int J Mol Sci Date: 2022-01-12 Impact factor: 5.923