The Discovery of Protheolysis Targeting Chimeras (PROTACs), Evolution, Design and Perspectives in Modulating Inflammatory Diseases

Currently, most drugs have their mode of action based on occupation-oriented pharmacology (proteins modulation through temporary inhibition by association and dissociation). Alternative modes of actions are welcome to exploit current known targets (in a more selective way, for example) as well as those known as “undruggable”. PROTAC (protheolysis targeting chimera) technology provides a compelling new approach that is based on an event-driven mode of action, exploring simultaneous binding to a protein and an E3 ligase, leading to targeted protein degradation, modulating the proteins levels. After all progress over the past two decades and the recent level of interest, clearly targeted protein degradation mode of action could become a therapeutic modality in the future. Furthermore, several PROTACs are under clinical trials, even already progressing to phase 3 (i.e., ARV-471). In this review we addressed the PROTACs discovery process, mode of action, evolution, current stage, their design, applications to modulating inflammatory conditions and the future directions of this promising drug discovery modality, including problems that still need to be overcome.

Keywords:
PROTAC; event-driven mode of action; undruggable targets; hybrid compounds; E3 ligase