Proteasome Inhibitors Versus E3 Ligase Inhibitors for Cancer Therapy

Molecular oncology has the potential to revolutionize cancer treatment owing to its focus on discrete, cancer-selective targets, as evident in the recent success of kinase inhibitors and antibody-based therapies. Because of the heterogeneous nature of cancer, however, not every tumor type can be addressed with an appropriately selective therapy and some respond best to drug combinations that include classical “toxic” agents. The ubiquitin-proteasome pathway, recently harnessed for cancer treatment with the clinical use of “toxic” proteasome inhibitors bortezomib and carfilzomib, affords targets that intuitively are highly selective, exemplified by inhibitors of E3 ligases, the ubiquitin-conjugating enzymes, as well as those that are intuitively nonselective, exemplified by the proteasomal proteases. In the last two decades, anticancer drug development based on these two target classes has proceeded in parallel, with the early results suggesting that the nonselective proteasome is the better target. Lately, however, it has become clear that (1) the “nonselective” proteasome target may be addressed in selective ways and (2) a clearer understanding of the E3 ligase reaction can lead to the design or discovery of efficacious inhibitors. Evidence supporting these notions and implications for cancer treatment going forward will be discussed.