Inhibition of mTOR by a small molecule activator of TSC2

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The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth. Commensurate with mTORC1's importance, a complex network of growth factor signaling and nutrient sensing pathways regulate mTORC1 activity, which in turn regulates protein synthesis and many other cellular processes. Hyperactivation of mTORC1 signaling is a common feature of the diseases and conditions of aging. mTORC1 inhibition is a promising treatment strategy for these diseases. mTORC1 inhibitors increase improve prevent cancer, decrease obesity and reverse age-related immune decline in humans and display activity in rodent models of neurodegeneration, cardiomyopathy, atheroscelerosis, retinopathy and hearing loss. mTORC1 inhibitors also increase lifespan in mice, worms and yeast. We have discovered a small molecule (CB3A) that inhibits mTORC1 signaling via a novel mechanism. Unlike other small molecule inhibitors of mTORC1, CB3A preferentially decreases the phosphorylation of 4EBP1 relative to S6K. Thus CB3A-inspired drugs may provide a therapeutic benefit for diseases/conditions where 4EBP1 phosphorylation is the driver. These diseases/conditions include cancer, diabetes and muscle loss. However, mTORC1 hyperactivation can derive from diverse underlying molecular mechanisms. Therefore the goal of this project is to elucidate the mechanism of CB3A action. This information is required to identify which diseases are most likely to respond to a CB3A-inspired treatment strategy. Our preliminary results show that CB3A increases the ubiquitination of the negative mTORC1 regulator TSC2. Although the regulation of TSC2 by phosphorylation is well recognized, little is known about the role of ubiquitination in TSC2/mTORC1 regulation. CB3A itself is unlikely to have therapeutic value, but understanding the mechanism of CB3A inhibition is likely to identify new potential targets as well as new facets of mTORC1 regulation.