Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Abstract

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

“…Therefore, targeting the HECT E3 ligase may be a potential treatment strategy for human cancers. However, compared with RING-type E3 ligases, studies on HECT-type E3 ligase inhibitors are few [ 3 ]. The neural precursor cell–expressed developmentally downregulated gene 4 (NEDD4) family is one of the most characteristic HECT-type E3 ligases, which include NEDD4, ITCH, WWP2, SMURF1, and SMURF2.…”

“…To date, RBR is the least frequently targeted class of E3 ligases among inhibitors [ 3 ]. The linear ubiquitin chain assembly complex (LUBAC), composed of three subunit proteins (HOIP, HOIL-1L, and SHARPIN), is a polyprotein E3 ligase of the RBR family [ 232 ].…”

“…The linear ubiquitin chain assembly complex (LUBAC), composed of three subunit proteins (HOIP, HOIL-1L, and SHARPIN), is a polyprotein E3 ligase of the RBR family [ 232 ]. LUBAC activity and mutation are associated with diffuse large B-cell lymphoma [ 3 ]. The small-molecule inhibitors HOIPIN-8 [ 9 ], BAY11-7082, and gliotoxin, as well as stapled helical alpha-peptides targeting the HOIP/HOIL-1L and HOIL-1L/SHARPIN interfaces, can inhibit the activity of LUBAC [ 232 ].…”

“…Ubiquitination is a classical type of protein posttranslational modification [ 1 , 2 ]. In this process, ubiquitin (a highly conserved 76-amino-acid polypeptide) covalently binds to the substrate and mediates its transfer to the 26S proteasome complex for degradation [ 3 , 4 ]. Ubiquitination is catalyzed by the signaling cascades of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) [ 5 ] and leads to the covalent binding of ubiquitin to the target protein [ 6 ].…”

“…E3 ubiquitin ligases, critical enzymes in the ubiquitination reaction, mediate the recognition of the substrate in the ubiquitin–proteasome system and determine the specificity of the ubiquitination reaction [ 13 ]. On the basis of their structural characteristics and action mechanism, they are classified into three families: the really interesting new gene (RING) domain, the homologous to the E6-associated protein carboxyl terminus (HECT) domain, and the RING-between-RING (RBR) types of E3 ligases [ 1 , 3 , 14 ]. After the E3 ligases bind to the E2-Ub complex and the substrate, the RING-type E3 ligases catalyze the direct transfer of ubiquitin from E2 to the lysine residue of the substrate [ 1 ].…”