SCF ubiquitin ligase-targeted therapies

Abstract

The ubiquitin–proteasome system (UPS) has links to numerous diseases, and the clinical success of proteasome inhibitors suggests the potential to develop drugs targeting other components of the UPS. In certain cases, the specific inhibition of individual components of the UPS may provide better therapeutic outcomes than does broad inhibition of the proteasome. F-box proteins are the targeting subunits of the SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes, the best characterized of the mammalian cullin–RING ligase family of E3 ubiquitin ligases. In mammals, there are approximately 70 F-box proteins, each thought to be able to target multiple substrates, facilitating the regulation of diverse cellular pathways. SCF complexes are dysregulated in several diseases by overexpression of the F-box protein, by mutation (genetic deletion or point mutations) of the F-box protein, or by disrupting the pathways that control F-box protein–substrate targeting. In cases in which an SCF complex is overactive, the inhibition of SCF-mediated degradation can be achieved via competitive inhibition between substrate and F-box protein, allosteric inhibition that disrupts the interaction between substrate and F-box protein, or via the inhibition of SCF complex assembly. In cases in which SCF activity is defective in disease, SCF activity can by reconstituted through bivalent small molecules that re-target the substrate and/or 'molecular glue'-like molecules that restore substrate–F-box protein binding. Although an underdeveloped area, SCF complexes are promising drug targets, and as the substrates and functions of orphan F-box proteins are discovered, further drug targets will become apparent. Several compounds targeting E3 ligases have been developed, hinting that effective drugs targeting other SCF ubiquitin ligase activities may also be developed.