Enabling Protein Degradation Drug Discovery

Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al., 2009). The deubiquitylating – or deubiquitinating – enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin dependent signalling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB, cysteine proteases and metalloproteases.  Ubiquitin specific protease 20 (USP20) is a member of the cysteine protease enzyme family and cloning of the gene was first described by Nagase et al. (1999). USP20 has been shown to specifically deubiquitylate and stabilise Hypoxia-inducible factor (HIF)-1α, increasing expression of HIF-1α targeted genes, such as vascular endothelial growth factor (VEGF) (Li et al., 2005). USP20 also deubiquitylates tumour necrosis receptor-associated factor 6 (TRAF6) and Tax and suppresses interleukin 1β (IL-1β) and Tax-induced NF-κB activation. Recent evidence has shown that USP20 overexpression may impede the proliferation of human T cell leukaemia virus type 1/adult T cell leukaemia (HTLV-1/ATL) cells and suggest that screening for small-molecule compounds to enhance USP20 deubiquitylase activity may unveil new agents that are useful for treating adult T cell leukaemia (Yasunaga et al., 2011).