Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Abstract

a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…Based on aberrant UPS activity frequently observed in human cancers, potential therapeutic targets have been identified, and corresponding inhibitors have been developed. 11,65,503 Currently, the proteasome is a successful target in the clinic, and good therapeutic results are achieved for some FDA-approved PIs, such as bortezomib, carfilzomib, oprozomib and ixazomib. However, as the last step of the ubiquitination process, these PIs can result in some side effects due to the accumulation of upstream ubiquitinated proteins, which limits their widespread application.…”

<p>RING Finger Protein 38 Mediates LIM Domain Binding 1 Degradation and Regulates Cell Growth in Colorectal Cancer</p>

“…4 Among them, the disorder of protein ubiquitination components is closely related to the occurrence and development of cancer. 5 At present, the research and development of new drugs targeting E3 ubiquitin ligase have become a research hotspot of scientists. 6 Therefore, the study of ubiquitination of proteins in colorectal cancer (CRC) cells is of great significance for the treatment of colorectal cancer caused by the disorder of ubiquitin system.…”

Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity

“…Since their effect is not limited by equilibrium occupancy, it results in less drug exposure and reduced toxicity compared with traditional inhibitors. Because of their improved and prolonged activity profile, they are increasingly used to develop more effective antitumor agents and other therapeutics [31][32][33] . Importantly, because PROTACs rely on E3 ligases to induce protein degradation, it is possible to achieve cell/tissue selectivity, even when the target proteins are ubiquitously expressed as long as they target the proteins to an E3 ligase that is cell-or tissue-specific.…”