From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Carlotta Cecchini; Sara Pannilunghi; Sébastien Tardy; Leonardo Scapozza

doi:10.3389/fchem.2021.672267

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Front Chem. 2021 Apr 20:9:672267. doi: 10.3389/fchem.2021.672267. eCollection 2021.

Authors

Carlotta Cecchini^{1

2}, Sara Pannilunghi^{1

2}, Sébastien Tardy^{1

2}, Leonardo Scapozza^{1

2}

Affiliations

¹ School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
² Pharmaceutical Biochemistry/Chemistry, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.

Abstract

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to the use of small-molecule inhibitors for knocking down classic targets and disease-related proteins classified, until now, as "undruggable." In early 2019, the first targeted protein degraders reached the clinic, drawing attention to PROTACs as one of the most appealing technology in the drug discovery landscape. Despite these promising results, PROTACs are often affected by poor cellular permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA). Herein, we report a comprehensive record of PROTAC design, pharmacology and thermodynamic challenges and solutions, as well as some of the available strategies to enhance cellular uptake, including suggestions of promising biological tools for the in vitro evaluation of PROTACs permeability toward successful protein degradation.

Keywords: PROTAC technology; cell permeability; drug discovery; protein degradation; proteolysis targeting chimeras; ubiquitin-proteasome system.

Publication types

Review