Glycoconjugation of Quinoline as an Effective Strategy for Selective Inhibition of mTORC1

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists as mTORC1/2 complexes and regulates crucial cellular metabolic processes. Dysregulation of mTOR signaling is implicated in numerous chronic diseases. Rapalogs display limited clinical applications as selective mTORC1 inhibitors due to adverse metabolic and immunological effects arising from off-target inhibition of mTORC2, thereby warranting newer selective mTORC1 inhibitors. Herein, we have developed quinoline glycoconjugates that exhibit potent and selective mTORC1 inhibition in both in vitro and in vivo murine models. Our designed compounds feature a C-6 functionalized quinoline core with a C-3 ethoxypropyne handle, conjugated to mono- and bisglyco ligands via a triazole linker using click chemistry. Lead compound TCG3 reduces cellular lipid accumulation and induces autophagy, with minimal or no cytotoxicity. These findings support TCG3 as a promising selective mTORC1 inhibitor with potential therapeutic applications and highlight the effectiveness of glycoconjugation in fine-tuning selectivity and cytotoxicity.