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

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:

• PROTAC
• posttranslational modifications
• E3 ubiquitin ligases
• proteasome degradation
• collateral degradation
• structure optimisation

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Additional information

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).