Ubiquilin Mediated Inhibition of mTOR Signaling (Brandeis Ref. 1236)

Mammalian target of rapamycin complex1 (mTORC1) is a master regulator of cellular growth and proliferation. Dysregulation of mTOR signaling is important in many diseases including cancer, neurodegeneration and diabetes. mTOR inhibition increases the lifespan in many organisms. We have discovered a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. This process is mediated by ubiquilins, thus linking mTOR signaling to protein homeostasis. Cbz-B3A preferentially inhibits the phosphorylation of certain binding proteins and blocks most of the translation process. Cbz-B3A slows cellular growth of human tumor cell lines, but is not cytotoxic. Cbz-B3A has very different characteristics than previously described mTOR inhibitors. It is a specific inhibitor of the mTORC1 complex, while rapamycin, TORIN and other inhibitors also block mTORC2. In contrast to rapamycin, which preferentially inhibits the phosphorylation of p70s6k, or TORIN, which inhibits the phosphorylation of all mTOR substrates. Cbz-B3A preferentially blocks the phosphorylation of 4EBP1. This property makes Cbz-B3A a more effective inhibitor of translation (68% versus 30% for rapamycin). The translation block is believed to be responsible for the prolongation of aging. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. Brandeis OTL is seeking statements of interest from parties interested in licensing and/or sponsoring collaborative research to further develop, evaluate, or commercialize this technology and its applications. Rajnish Kaushik Rajnish@Brandeis.edu 781-736-4220

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