Proteolysis Targeting Chimeras (PROTACs): An Innovative Strategy for Targeted Protein Degradation and Disease Treatment

Abstract

Review Proteolysis Targeting Chimeras (PROTACs): An Innovative Strategy for Targeted Protein Degradation and Disease Treatment Jun Xia, James K.S. Norris, May-Li MacKinnon and Sam Butterworth * Division of Pharmacy and Optometry, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9PL, UK * Correspondence: sam.butterworth@manchester.ac.uk Received: 18 May 2024; Revised: 9 Jule 2024; Accepted: 9 Jule 2024; Published: 26 August 2024 Abstract: Protein ubiquitination is a highly conserved post-translational modification through which cells initiate the proteasomal degradation of undesired, aberrant, or damaged proteins. Protein ubiquitination plays a crucial role in protein homeostasis and regulates a wide range of essential physiological processes including DNA repair, immunological response, cell survival and apoptosis. Dysregulation of ubiquitination is associated with various pathologies including cancers, neurodegenerative diseases, and immune disorders. The ubiquitin-proteasome system (UPS) machinery has been utilized in therapeutic research as it can be manipulated to induce the degradation of undruggable proteins in a superior manner to traditional drug modalities. One such a method of specific protein degradation is the use of heterobifunctional molecules such as proteolysis targeting chimeras (PROTACs). This literature review will focus on the composition, mechanism of action and developmental milestones of PROTACs, comparing these against traditional drug discovery and treatment approaches. In addition, the potential benefits of PROTAC usage will be highlighted by analyzing their practical applications in drug therapies.