Discovering Proteasomal Deubiquitinating Enzyme Inhibitors for Cancer Therapy: Lessons From Rational design, Nature and Old Drug Reposition

Abstract

The ubiquitin proteasome system has been validated as a target of cancer therapies evident by the US FDA approval of anticancer 20S proteasome inhibitors. Deubiquitinating enzymes (DUBs), an essential component of the ubiquitin proteasome system, regulate cellular processes through the removal of ubiquitin from ubiquitinated-tagged proteins. The deubiquitination process has been linked with cancer and other pathologies. As such, the study of proteasomal DUBs and their inhibitors has garnered interest as a novel strategy to improve current cancer therapies, especially for cancers resistant to 20S proteasome inhibitors. This article reviews proteasomal DUB inhibitors in the context of: discovery through rational design approach, discovery from searching natural products and discovery from repurposing old drugs, and offers a future perspective.

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

“…Especially the development of UPS inhibitors, targeting an array of components of the ubiquitin-proteasome system, has been a focal point of extensive research in recent years. Additionally the development of proteasomal DUB inhibitors has generated increasing interest [256]. Potential targets within the UPS are abundant, and research has been done on a multitude of its components.…”

Inhibition of Ubiquitin Specific Protease 1 Sensitizes Colorectal Cancer Cells to DNA-Damaging Chemotherapeutics

“…Despite extensive efforts, the only inhibitor undergoing clinical trials is nutlin-3, which blocks the interaction of p53 with its E3 Mdm2 (28). Due to their critical roles in many cellular processes, it has been proposed that targeting DUBs represents an effective and relative specific means to modulate the activities of the ubiquitinproteasome system (29). The well-defined catalytic mechanisms of various DUBs also make it possible to develop a variety of apparently druggable inhibitors (30).…”

The role of ubiquitin-specific peptidases in cancer progression

“…Herein we discussed how to develop a specific inhibitor of USPs. The development of USP inhibitors has resulted in a range of small molecule inhibitors and has been summarized in previous reviews [104,105]. Many identified USP inhibitors have been suggested to have paninhibitory activity [104,105].…”

“…The development of USP inhibitors has resulted in a range of small molecule inhibitors and has been summarized in previous reviews [104,105]. Many identified USP inhibitors have been suggested to have paninhibitory activity [104,105]. For example, compound WP1130 has a broad panenzymatic DUB profile and can directly inhibit USP9x, USP5 and USP14 [106,107].…”