Abstract
Simple SummaryThe ubiquitin-proteasome system regulates multiple facets of protein homeostasis to modulate signal transduction in numerous biological processes. Not surprisingly, dysregulation of this delicately balanced system is frequently observed in cancer progression. In the past two decades, researchers in both academia and industry have made significant progress in developing small-molecule inhibitors targeting various components in the ubiquitin-proteasome system for cancer therapy. Here, we aim to provide a comprehensive summary of these efforts. Additionally, we overview the advancements of targeted protein degradation, a recently emerging drug discovery concept in cancer therapy.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.
Highlights
The ubiquitin-proteasome system (UPS) is vital for protein homeostasis and is implicated in many cellular processes, including DNA repair [1], endocytic trafficking [2], and the immune response [3]
The wide range of activities regulated by the UPS stems from the remarkable specificity and diversity of signal transduction events enabled by the process of ubiquitination
The UPS is a rich resource of attractive targets for developing cancer therapeutics due to its essential role in controlling protein homeostasis
Summary
The ubiquitin-proteasome system (UPS) is vital for protein homeostasis and is implicated in many cellular processes, including DNA repair [1], endocytic trafficking [2], and the immune response [3]. In the presence of ATP, Ub is activated by E1 before being delivered to the E2 enzyme, and this is followed by its eventual transfer to the substrate proteins, catalyzed by a E3 ligase [5,7]. Ub is reversibly conjugated either at a lysine (K) residue or an N-terminal amino acid. Ub is reversibly conjugated either at a lysine (K) residue or an N-terminal amino acid and and be attached as a single polypeptide (mono-ubiquitination) or a polymer at can can be attached as a single polypeptide or a polymer of at leastoffour least four (poly-ubiquitination) [4,7,8,9,10].
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