Exploring the Ubiquitin-Proteasome System (UPS) through PROTAC Technology

Abstract

In the context of dysregulated ubiquitylation, the accumulation of oncogenic substrates can lead to tumorigenesis. In particular, mutations in Von Hippel-Lindau (VHL) E3 ubiquitin ligase are related to overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α) which is evolving into renal cell carcinoma (RCC). The classical approach of drug discovery focuses on the development of highly selective small molecules able to bind and to inhibit enzymatic active sites. This strategy faces limitations in the context of ' undruggable ' proteins, which are challenging to target. The discovery of Proteolysis Targeting Chimeras (PROTACs) as an alternative strategy to induce selective protein degradation is presented as a working hypothesis to understand further the UbiquitinProteasome System (UPS) and eventually counteract RCC cancer lacking VHL ubiquitin ligase.

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

“…From a structural point of view, PROTAC design relies on the combination of three different chemical moieties: an E3 ligase binder, a target of interest (TOI) ligand, and a linker, which connects the two parts (Figure 1). Finding the best combination for these three elements requires an attentive study of the structural characteristics of the E3 ligase and the TOI complemented by molecular modeling and dynamics (Westermaier et al, 2015;Cecchini et al, 2020). In particular, the spatial orientation and the alignment of both elements allow the formation of a ternary complex and are crucial for an FIGURE 1 | Targeted protein degradation by PROTACs.…”

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…Unequivocally, HIF-1α has a central role in orchestrating the processes that allow cancer cells (and other diseased cells) to accommodate aerobic glycolysis [108,109]. Under normoxic conditions, in which most cells exist, HIF-1α subunits are ubiquitinated by the von Hippel-Landau complex and quickly undergo proteasomal degradation, so it has little effect on glucose metabolism or oxidation [110,111]. Under hypoxic conditions, HIF-1α is not polyubiquitinated so it is not degraded by the proteosome; thus, it becomes available for manipulating glucose metabolism.…”

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

“…Several entities revealed promising activity in various diseases in the preclinical setting and recently entered clinical trials in human patients . As discussed in several of the latest reviews on the topic of chimeric degraders, − very few E3 ligases are utilized with this technology. These include cullin-RING E3 ubiquitin ligases (CRL), cereblon (CRBN), and von Hippel–Lindau.…”