Open AccessExploring the Ubiquitin-Proteasome System (UPS) through PROTAC Technology
Author(s) -
Carlotta Cecchini,
Sébastien Tardy,
Valentina Ceserani,
Jean-Philippe Theurillat,
Léonardo Scapozza
Publication year - 2020
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2020.274
Subject(s) - ubiquitin ligase , ubiquitin , proteasome , context (archaeology) , drug discovery , proteolysis , carcinogenesis , dna ligase , protein degradation , biology , microbiology and biotechnology , ubiquitin protein ligases , computational biology , chemistry , cancer research , cancer , biochemistry , enzyme , genetics , gene , paleontology
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? and HIF-2?) 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.