The step before NF-κB leaves the cytoplasm involves the ubiquitination of IκB by the SCF-β-TrCP ubiquitin ligase complex followed by the rapid degradation of ubiquitinated IκB by the 26S proteasome [38]. Because IκBα degradation is an important step in the NF-κB activation pathway, inhibiting the proteasomes that degrade IκBα may also serve as a tool for pharmacological intervention. Very specific and potent proteasome inhibitors have been engineered by coupling boronic acid to dipeptides [81]. The dipeptide boronate, bortezomib, the most-studied proteasome inhibitor in clinical development [82], has been shown to inhibit proliferation and induce apoptosis in head and neck [83–85], prostate [86], pancreatic [87], gastric [88], and ovarian [89] cancers. Bortezomib’s antitumor properties correlate in part with its ability to inhibit IκBα degradation [83, 90]. Other well-known proteasome inhibitors include ALLnL, LLM, Z-LLnV, and Z-LLL, lactacystine, N-cbz-Leu-Leu-leucinal (MG132), MG115, and ubiquitin ligase inhibitors [91]. In addition, we recently identified a novel proteasome inhibitor, salinosporamide A (NPI-0052), which can suppress both constitutive and inducible NF-κB activation in a nanomolar range [92].
