Selective mTORC1 Inhibitors to Treat TSC
Abstract
Tuberous sclerosis complex (TSC) is a rare, genetic and chronic disease that appears in early childhood. TSC is characterized by increased activity of the protein mTOR, which can cause tumors in various organs, skin lesions, epileptic seizures, and cognitive disabilities. By binding different partners, mTOR forms two different protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Increased activity of mTORC1 (and not of mTORC2) is the specific cause of TSC. Several drugs reducing mTOR activity (mTOR inhibitors) are used in the clinic for the chronic treatment of TSC. However, they cause undesirable side effects such as high blood glucose and insulin resistance (linked to diabetes) and high cholesterol. This is because mTOR inhibitors fail to distinguish between mTORC1 and mTORC2 and eventually reduce the function of not only mTORC1 but also of mTORC2. Reduction of mTORC2 function is the cause of the abovementioned side effects. Thus, the optimal approach for the treatment TSC through mTOR activity reduction would be a regimen that reduces only mTORC1 activity without reducing mTORC2 activity. Our ultimate goal is to develop new therapeutics for the treatment of TSC based on reducing only mTORC1 activity (selective mTORC1 inhibition). Our preliminary work has identified some promising selective mTORC1 inhibitors. During this study, we aim to continue developing them and to study if and how they reduce mTORC1 activity in cultured cells and mouse models of TSC. This project will help us bring our selective mTORC1 inhibitors toward clinical trials and will eventually lead to better therapeutics for TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210282
Entities
People
- Michael N. Hall
Organizations
- United States Army
- University of Basel