Protac: redirecting protein degradation systems to new substrates

Abstract

The small molecules development has dominated the design of new drugs until the rise of nucleic acid-based therapies, either by modifying a gene or by preventing it from being effectively transcribed. Taking advantage of this new approaches, the pharmacological intervention in therapeutic targets that are considered unmodifiable up to now with small molecules were allowed. However, these new approaches are not devoid of defects such as low bioavailability due to their stability and pharmacokinetic problems, in addition to being irreversible DNA modifications in many cases, with the subsequent risk of suffering chronic adverse effects. Alternatively, a series of chimeric heterobifunctional compounds, called PROTACs (Protein Targeting Chimeras), have emerged with force in recent years. These PROTACs are able to bring E3 ligases closer with proteins of interest in space to label them with ubiquitin. Finally, it was degraded by the proteasome. This approach enables the generation of different PROTACs structures by rational design and, also, allows the chemical structure modification to improve their stability and pharmacokinetic profile keeping their activity. This review aims to give a comprehensive approach of what PROTACs are, what E3 ligases recruit, relevant factors in PROTAC development, and other approaches similar to this but that use non-proteasomal degradation pathways.