Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor

The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyper-activation of the mTOR pathway in human cancers2, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based platform to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor of the SCF(Met30) ubiquitin ligase (SMER3). The large SCF (Skp1-Cullin-F-box) family of ubiquitin ligases performs important functions in diverse cellular processes including transcription, cell-cycle control, and immune response3. Accordingly, there would be great value in developing SCF ligase inhibitors that act by a defined mechanism to specifically inactivate ligase activity. We show here that SMER3 selectively inhibits SCF(Met30 )in vivo and in vitro, but not the closely related SCF(Cdc4). Our results demonstrate that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes, and suggest new strategies for combination therapy with rapamycin.