Deubiquitylating enzymes and drug discovery: emerging opportunities

Abstract

| More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitinproteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.

Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis

“…Due to their relevance in the regulation of essential cell processes, the development of inhibitors for DUBs is an attractive, yet challenging research area [17] .…”

“…DUBs contain a well-defined active site mostly with a catalytic cysteine [17] , making them prone to inhibition by covalent modification of the active-site residue. Covalent inhibitors may have advantages over classic non-covalent inhibitors such as increased potency and longer residence times.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy‐based enzyme inhibition approaches . Small‐molecular‐weight synthetic PROTACs ( 185‐189 ) have been used to selectively degrade various specific proteins (Figure ), including pirin, sirt2, BET protein, androgen receptor, and BRD4 protein …”

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

“…Deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by removing ubiquitin from target proteins and are also involved in ubiquitin maturation, recycling and editing (Pfoh et al, 2015; Singh and Singh, 2016; Harrigan et al, 2018). The human genome encodes ~100 DUBs.…”

“…Based on the mechanism of enzymatic cleavage, DUBs can be divided into two main classes: cysteine proteases and zinc metalloproteases. Based on sequence and domain conservation, DUBs can also be divided into six subfamilies: ubiquitin-specific proteases (USPs), ovarian-tumor proteases (OTUs), Machado–Joseph disease protein domain proteases (MJDs), ubiquitin carboxy-terminal hydrolases (UCHs), monocyte chemotactic protein-induced protein (MCPIP) and JAMM/MPN domain-associated metallopeptidases (JAMMs) (D'Arcy et al, 2015; Pfoh et al, 2015; Kemp, 2016; Harrigan et al, 2018). Among these DUBs, USPs are the most numerous classes with ~60 proteases in humans, with sizes ranging from 50 to 300 kDa (Pfoh et al, 2015).…”