SCF ubiquitin ligase-targeted therapies

Abstract

Summary The recent clinical successes of inhibitors of the proteasome for the treatment of cancer have highlighted the therapeutic potential of this protein degradation system. Proteasome inhibitors prevent the degradation of numerous proteins, so increased specificity could be achieved by inhibiting the components of the ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a large number of processes at the cellular and organismal levels, and their misregulation is implicated in many pathologies. SCF ligases are characterized by a high specificity for their substrates, so they represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This review will explore and discuss potential strategies to target SCF-mediated biology to treat human diseases.

The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin

“…Nevertheless, the results of these studies might be important in the design, synthesis, and testing of small-molecule antagonists to F-box subunits that might be injurious through activation of cell death effector pathways. Such small-molecule-targeted therapeutics are already in preclinical testing (23)(24)(25)(26)(27)(28).…”

EGFR and NF-κB: partners in cancer

“…Proteasome inhibition actually enhanced MAPK, AKT, and STAT3 prosurvival pathways through both EGFR-dependent and -independent mechanisms [67]. These studies highlighted the need to design new combinatorial approaches by using a morespecific NF-kB inhibitor than bortezomib, which blocks the degradation of IkBa as well as of numerous other proteins, including key oncogenic products [68]. Interestingly, both IKKa and IKKb are aberrantly activated in HNSCC, act as mediators of NF-kB activation, and enhance EGFR signaling in HNSCC [43].…”

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…Novel compounds targeting F‐box proteins have been developed, and therefore, F‐box proteins represent candidate pharmacological targets to treat cancer (Skaar et al , 2014). However, few F‐box proteins have been matched to substrates and biological roles.…”