Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase

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Abstract
Although general inhibitors of the ubiquitin-proteasome system have been reported, compounds targeting specific ubiquitylation enzymes should be beneficial in clinical applications and basic research. Aghajan et al. present an inhibitor of the yeast SCFMet30 E3 ligase that prevents the binding of the Met30 F-box protein to the core ligase complex. The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyperactivation of the mammalian TOR (mTOR) pathway in human cancers2, strategies to enhance TOR pathway inhibition are needed. We used a yeast-based screen to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor (SMER3) of the Skp1-Cullin-F-box (SCF)Met30 ubiquitin ligase, a member of the SCF E3-ligase family, which regulates diverse cellular processes including transcription, cell-cycle control and immune response3. We show here that SMER3 inhibits SCFMet30 in vivo and in vitro, but not the closely related SCFCdc4. Furthermore, we demonstrate that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and show evidence for SMER3 directly binding to Met30. Our results show that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes.