INTRODUCTION: Deubiquitinating-enzymes (DUBs) are key components of the ubiquitin-proteasome system (UPS). The fundamental role of DUBs is specific removal of ubiquitin from substrates. DUBs contribute to activation/deactivation, recycling and localization of numerous regulatory proteins, and thus play major roles in diverse cellular processes. Altered DUB activity is associated with a multitudes of pathologies including cancer. Therefore, DUBs represent novel candidates for target-directed drug development. AREAS COVERED: The article is a thorough review/accounting of patented compounds targeting DUBs and stratifying/classifying the patented compounds based on: chemical-structures, nucleic-acid compositions, modes-of-action, and targeting sites. The review provides a brief background on the UPS and the involvement of DUBs. Furthermore, methods for assessing efficacy and potential pharmacological utility of DUB inhibitor (DUBi) are discussed. EXPERT OPINION: The FDA's approval of the 20S proteasome inhibitors (PIs): bortezomib and carfilzomib for treatment of hematological malignancies established the UPS as an anti-cancer target. Unfortunately, many patients are inherently resistant or develop resistance to PIs. One potential strategy to combat PI resistance is targeting upstream components of the UPS such as DUBs. DUBs represent a promising potential therapeutic target due to their critical roles in various cellular processes including protein turnover, localization and cellular homeostasis. While considerable efforts have been undertaken to develop DUB modulators, significant advancements are necessary to move DUBis into the clinic.

Barbara Ann Karmanos Cancer Institute School of Medicine Wayne State University Detroit Michigan USA

Department of Cell Biology and Genetics Palacky University Slechtitelu 11 Olomouc 78371 Czech Republic

Department of Medical Biochemistry Faculty of Basic Medical Sciences Federal University Ndufu Alike Ikwo Ebonyi State Nigeria

Department of Oncology School of Medicine Wayne State University Detroit Michigan USA

Department of Pathology School of Medicine Wayne State University Detroit Michigan USA

Department of Pharmacology School of Medicine Wayne State University Detroit Michigan USA

State Key Lab of Respiratory Disease Protein Modification and Degradation Lab Department of Pathophysiology Guangzhou Medical University Guangdong 510182 China

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USP8 inhibition regulates autophagy flux and controls Salmonella infection