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.