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Growth control by the TOR signalling network

Final Report Summary - TOR SIGNALLING (Growth control by the TOR signalling network)

The Target Of Rapamycin (TOR) is a Ser/Thr protein kinase first discovered in studies with the model eukaryote Saccharomyces cerevisia (brewers’ yeast). TOR assembles into two, distinct multiprotein complexes known as TORC1 and TORC2. These complexes are conserved from yeast to man but only TORC1 is acutely inhibited by the bacterial secondary metabolite rapamycin. Mammalian TORC1 is a validated drug target in immunosuppression, cardiovascular procedures and oncology and preclinical data suggest that targeting of mTORC2 may also be useful in some clinical settings. In this ERC grant we proposed to identify small molecule inhibitors of TORC2 signaling. Such compounds would be of certain use as tools to dissect TOR functions in vivo and also as potential therapeutic leads. To this end we established a robust screening protocol designed to identify drug-like small molecules that specifically inhibit TORC1 and/or TORC2 in yeast. Successful completion of high and ultra-high throughput screens yielded two novel ATP-competitive TORC1/2 inhibitors and several compounds that appear to affect TORC signaling upstream of the complexes themselves. While these later compounds are still being characterized, the former have served, and continue to serve as useful tool compounds for example by allowing us to define the TORC2-dependent phosphoproteome in yeast and to identify TORC2 as a major regulator of the tensile homeostasis of the plasma membrane in Eukaryotes.


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