Structural considerations and chemistry of protacs

Abstract

The druggability of protein targets and dose-dependent side effects present challenges to the search for efficient therapies through enzyme inhibition. The druggability of protein targets and dose-dependent side effects present challenges to the search for efficient therapies through enzyme inhibition. The ubiquitin-proteasome system (UPS) has gained attention as a way to specifically break down target proteins as a result of this problem. One interesting approach is the use of target-based degradation (TBD) approaches, such as proteolysis-targeting chimeras (PROTACs). PROTACs are heterobifunctional molecules that recruit specific proteins for UPS-mediated degradation, bypassing the need to target active sites. Since their inception in 2001, PROTACs have evolved significantly, enabling the degradation of previously deemed ‘undruggable’ proteins. This chapter reviews the development and mechanisms of PROTACs, highlighting milestones such as the first cell-permeable PROTAC and the advent of small molecule-based E3 recruitment ligands. Notably, PROTACs have demonstrated efficacy in preclinical models, showcasing their potential in treating diseases including cancer and neurodegenerative disorders. With over 600 publications dedicated to PROTAC research, this chapter provides a comprehensive overview of their structural considerations and design principles, underscoring their pivotal role in contemporary drug development.