The mTOR protein is a key regulator of how cells sense nutrients and energy and adapt their growth and metabolism accordingly. When the activity of one of its functional forms, mTORC1, is improperly controlled, it contributes to many major health problems, including cancer, metabolic diseases, and ageing-related conditions. For this reason, mTORC1 has long been considered an important target for drug development. However, current drugs that inhibit mTOR have significant limitations. Some only partially block mTORC1 and are therefore not sufficiently effective, while others inhibit multiple mTOR-related pathways at once, often leading to unwanted side effects. There is thus a clear need for new compounds that more effectively and more selectively inhibit mTORC1. This project builds on the discovery that a naturally occurring molecule can directly inhibit mTORC1 inside cells (Nicastro et al. 2023 Nat Cell Biol, PMID: 37563253), revealing a new way in which metabolism can control this important signalling pathway. Although this natural molecule itself is not suitable for therapeutic use, it provides a valuable starting point for developing improved synthetic compounds. The overall objective of the project was to use this discovery to develop and test new molecules with enhanced potency and a stronger preference for mTORC1 inhibition compared to existing drugs. By combining computational design, chemical synthesis, and biological testing, the project aimed to generate promising candidate compounds for future development. The expected impact of the project is to establish the basis for a new class of mTORC1-targeted inhibitors with potential applications in ageing and disease. These results provide a foundation for further optimization, intellectual property generation, and longer-term translational and commercial exploitation.
