Exploiting Cellular Metabolism to Develop the Next Generation of mTOR Inhibitors

The mTOR (mammalian/mechanistic Target of Rapamycin) kinase, as part of the mTORC1 and mTORC2 protein complexes, is the master controller of cellular and organismal physiology. Dysregulation of mTORC1 activity is tightly linked to human disease and ageing.

Consequently, mTOR inhibitors have been tested in various clinical settings, however with little success and limited applicability so far, mainly due to low efficacy or adverse effects, thus highlighting the need for more potent and more specific compounds. For instance, the phosphorylation of most mTORC1 targets is resistant to rapamycin and its analogs (rapalogs).

Furthermore, catalytic mTOR inhibitors demonstrate increased toxicity and cause unwanted metabolic effects mainly because they also block mTORC2 activity.

We have recently identified malonyl-CoA, a metabolic intermediate of fatty acid biosynthesis, as a novel specific mTORC1 inhibitor in cells that shows improved characteristics over existing compounds as it blocks phosphorylation of all mTORC1 targets without affecting the activity of mTORC2 or other related kinases.

Using our biochemical, structural and computational data as the basis for targeted compound development, we aim to develop synthetic malonyl-CoA derivatives as a new class of mTORC1 inhibitors with improved specificity and effectiveness.

Because of the well-established role of mTORC1 in ageing and disease, these inhibitors are expected to be of profound scientific, clinical, and commercial interest.