Targeted degradation of undruggable, malignant haematological disorder-causing proteins using bifunctional molecules, exploiting polyubiquitination and degradation in proteasomes

Czech version

Authors: O. Fuchs; R. Bokorová
Authors‘ workplace: Ústav hematologie a krevní transfuze, Praha
Published in: Transfuze Hematol. dnes,26, 2020, No. 4, p. 292-301.
Category: Review/Educational Papers

Overview

Inhibition of proteins with small-molecule inhibitors is restricted to receptors and enzymes which make up approximately 25% of the human proteome. The majority of proteins such as transcription factors, scaffolding proteins, regulatory proteins and non-enzymatic proteins are difficult (“undruggable“) targets for small-molecule inhibitors. In the past 20 years, new procedures have been developed based on the mechanism of inducible protein degradation that exploits polyubiquitination and degradation in proteasomes using proteolysis targeting chimeras (PROTACs). Bifunctional molecules (PROTACs) are composed of specific ligand for the protein of interest connected via a linker to a specific ligand for E3 ubiquitin ligase used in protein of interest polyubiquitination and its subsequent degradation in proteasomes. The presented bifunctional molecules have been successfully used experimentally in degradation of many proteins of interest that have important functions in the pathogenesis of haematological malignancies and are the subject of this review.

Keywords:

protein degradation – proteolysis-targeting chimera (PROTAC) – ubiquitin – proteasome – E3 ubiquitin ligase

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