Posted March 18, 2022

Dr. Michael Hall, University of Basel, Switzerland

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disease. TSC patients harbor loss-of-function mutations in one of the tumor suppressor genes TSC1 and TSC2, making the protein kinase mammalian target of rapamycin complex 1 (mTORC1) constitutively active and thereby causing uncontrolled cell growth. As TSC arises from this unbridled mTORC1 activity, mTORC1 inhibitors (rapalogs) are commonly used to treat several TSC manifestations such as renal, lung, and brain tumors (angiomyolipomas, lymphangioleiomyomatosis, subependymal giant cell astrocytomas, respectively) partial onset seizures in children, and facial tumors (angiofibroma). However, over time rapalogs can show limited effectiveness, partial selectivity, and reduced safety. Since TSC patients need to be treated chronically, developing more effective treatment options for TSC symptoms is of utmost interest and would have a profound impact on TSC patients.

In fiscal year 2019 (FY19), Dr. Michael Hall, at the University of Basel in Switzerland, received an Exploration - Hypothesis Development Award from the Tuberous Sclerosis Complex Research Program (TSCRP) to investigate novel mTORC1 inhibitors to treat TSC. The aims of the project were to confirm the functional consequence of selective mTORC1 inhibition on the TSC-mTORC1 signaling pathway at a cellular level, to identify novel selective mTORC1 inhibitors, and to determine their efficacy on mTORC1 activity in TSC1/2-deficient cell lines. Over the course of this award, Dr. Hall's group, spearheaded by Drs. Imseng and Gonzalez, identified a novel, rapalog-unrelated, druggable site on mTORC1 and identified that perturbing this novel site reduces mTORC1's ability to phosphorylate substrates in cultured cells. The group has continued the development of a novel class of selective mTORC1 inhibitors and has identified six compounds that selectively inhibit mTORC1 in vitro. These compounds are potential selective mTORC1 inhibitors and promising candidates for chemical and pharmaceutical development. This groundwork may lead to a new generation of selective mTORC1 inhibitors that could lead to novel treatment options for TSC as well as other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of mTORC1 inhibitors.

Dr. Hall will continue to build on this work with additional support from the TSCRP in the form of a new FY21 Idea Development Award, titled �Selective mTORC1 Inhibitors to Treat TSC.� The aims of this study are to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity and to determine if the optimized compounds selectively inhibit mTORC1 and exhibit tumor-reducing abilities in mice.

Dr. Hall asserts that, �[t]he clinical potential of these novel compounds is immense and readily testable. We believe our approach could be an important development, as we predict it to be more effective, selective, and safer in the treatment of TSC symptoms. Innovative treatments with better efficacy and safety will ameliorate TSC symptoms. Novel mTORC1-targeted drugs with reduced mTORC2-associated side effects would greatly improve the health and quality of life of TSC patients.�

Exploring and developing novel mechanisms for selective mTORC1 inhibition by targeting mTORC1-specific functions have allowed Dr. Hall's group to gain fundamental insights into the TSC-mTOR signaling pathway. Understanding the cellular pathways that drive different TSC manifestations will lead to innovative treatments with better efficacy and safety to ameliorate TSC symptoms.

Links:

Public and Technical Abstracts: Novel mTORC1 Inhibitors to Treat TSC

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