Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues

Marta Pichlak; Tomasz Sobierajski; Katarzyna M Błażewska; Edyta Gendaszewska-Darmach

doi:10.1080/14756366.2023.2254012

Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2254012. doi: 10.1080/14756366.2023.2254012.

Authors

Marta Pichlak¹, Tomasz Sobierajski², Katarzyna M Błażewska², Edyta Gendaszewska-Darmach¹

Affiliations

¹ Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Łódź, Poland.
² Institute of Organic Chemistry, Lodz University of Technology, Łódź, Poland.

Abstract

PROTACs represent an emerging field in medicinal chemistry, which has already led to the development of compounds that reached clinical studies. Posttranslational modifications contribute to the complexity of proteomes, with 2846 disease-associated sites. PROTAC field is very advanced in targeting kinases, while its use for enzymes mediating posttranslational modifications of the basic amino acid residues, started to be developed recently. Therefore, we bring together this less popular class of PROTACs, targeting lysine acetyltransferases/deacetylases, lysine and arginine methyltransferases, ADP-ribosyltransferases, E3 ligases, and ubiquitin-specific proteases. We put special emphasis on structural aspects of PROTAC elements to facilitate the lengthy experimental endeavours directed towards developing PROTACs. We will cover the period from the inception of the field, 2017, to April 2023.

Keywords: E3 ubiquitin ligases; PROTAC; collateral degradation; posttranslational modifications; proteasome degradation; structure optimisation.

Publication types

Review

MeSH terms

Arginine
Lysine*
Protein Processing, Post-Translational
Proteolysis Targeting Chimera*
Ubiquitin-Protein Ligases

Substances

Lysine
Proteolysis Targeting Chimera
Arginine
Ubiquitin-Protein Ligases

Grants and funding

This work was financially supported by the National Science Centre, Poland grants: PRELUDIUM BIS (2020/39/O/NZ1/02418 to EGD) and PRELUDIUM BIS (2020/39/O/ST4/01360 to KB).