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.
Highlights
The use of small-molecules for target modulation represents a classical approach in drug discovery, with a proven track record up to clinical use on a plethora of biological targets
The advent of Proteolysis Targeting Chimeras (PROTACs) technology to selectively degrade drivers of human diseases has opened up new promising perspectives in drug discovery, by offering possible solutions to overcome limitations related to the current drug development paradigm
The sub-stoichiometric mode-of-action, the possibility of targeting proteins previously considered “undruggable,” and the increased resilience to resistance mechanisms are some of the key features that affirm PROTACs success over smallmolecule inhibitors
Summary
The use of small-molecules for target modulation represents a classical approach in drug discovery, with a proven track record up to clinical use on a plethora of biological targets. PROTACs are heterobifunctional molecules able to bind a target protein and induce its degradation by recruiting a given E3 ubiquitin ligase (Bondeson et al, 2015, 2018).
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