Friend or Foe: UCHL3 Mediated Carcinogenesis and Current Approaches in Small Molecule Inhibitors’ Development

As cancer continues to be one of the leading causes of death, various cancer treatments are being developed from traditional surgery to the more recent emergence of target therapy. However, therapy resistance is a restricting problem that needs to be overcome. Henceforth, the field of research shifts to new plausible drug targets, among which is the ubiquitin-proteasome system. This review is focused on the ubiquitin carboxyl-terminal hydrolase (UCH) protease family, which are members of Deubiquitinating enzymes (DUBs), specifically Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3). DUBs regulate a broad array of regulatory processes, including cell-cycle progression, tissue development, and differentiation. DUBs are classified into seven subfamilies, including ubiquitin-specific proteases (USPs), JAB1/MPN/Mov34 metalloenzyme, ovarian tumor proteases (OTUs), Josephin and JAB1/MPN+(MJP), MIU-containing novel DUB (MINDY), zinc finger-containing ubiquitin peptidase 1 (ZUP1), and ubiquitin C-terminal hydrolases (UCHs). Having a significant role in tumorigenesis, UCHL3 is thus emerging as a therapeutic target. Knowing its involvement in cancer, it is important to understand the structure of UCHL3, its substrate specificity, and interaction to pave the way for the development of potential inhibitors. This review covers several directions of proteasome inhibitors drug discovery and small molecule inhibitors development.