Journal
CHIMIA
Volume 74, Issue 4, Pages 274-277Publisher
SWISS CHEMICAL SOC
DOI: 10.2533/chimia.2020.274
Keywords
Protein degradation; Proteolysis Targeting Chimeras; Renal cell carcinoma; Ubiquitylation
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Funding
- Swiss Chemical Society
- Swiss National Science Foundation (SNSF) [CRSII5_186405/1]
- DMS
- Swiss National Science Foundation (SNF) [CRSII5_186405] Funding Source: Swiss National Science Foundation (SNF)
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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-1 alpha and HIF-2 alpha) 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 Ubiquitin-Proteasome System (UPS) and eventually counteract RCC cancer lacking VHL ubiquitin ligase.
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