Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

Abstract

The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955-66. Ó2014 AACR.

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

“…11 This inhibitor illustrates an emerging class of therapeutics directed against DUBs for the treatment of cancer. 12 Here, we demonstrate 2 findings. First, USP9X inhibition increases radiation-induced apoptosis in NSCLC cells, showing its potential to improve treatment of a solid malignancy.…”

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

“…This is certainly a mechanistic departure from other DUB inhibitors that either directly target the active site Cys or interfere through binding at allosteric sites. 27 To exploit the Usp9x/Usp24 dual inhibitory activity of WP1130, we improved its activity and drug-like properties. G9 was more effective than WP1130 in Usp9x inhibition and Mcl-1 destruction and had an improved therapeutic index against myeloma vs normal CD34 1 cells (supplemental Figure 3C).…”

Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer

“…Therapeutic benefit with reduced toxicity might be obtained by targeting more specific aspects of the UPS. For example, Ub-specific proteases, an extensive class of de-ubiquitinating enzymes, have promise as therapeutic targets (15). Of comparable interest and specificity are the E3 Ub ligases, especially as key proteins commonly associated with proliferation and cell-cycle arrest (such as p53, p27, Cyclins, and NF-kB) are specifically regulated by these enzymes (16).…”