Tuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii.