PROTAC-induced proteolytic targeting

Abstract

Small-molecule modulators of protein activity are increasingly being utilized as tools to examine the functional roles of proteins. Operating at the post-translational level, these molecules provide enhanced temporal and spatial control and mitigate the potential for compensatory responses in comparison with classical genetic approaches. Proteolysis targeting chimeric molecules, or PROTACs, are small molecules that inhibit the function of their target proteins by targeting them for degradation by the ubiquitin proteasome system. This chapter summarizes strategies for PROTAC preparation and characterization.

Fig.1

PROTAC-induced degradation of a target protein via the UPS. PROTAC is a heterochimeric molecule composed of an E3 ubiquitin ligase recognition motif on one end and a small-molecule ligand for a target protein on the other end. PROTAC recruits a targeted protein to an E3 ligase complex for ubiquitination and degradation by the proteasome.

Fig.2

PROTAC synthesis strategy. Chimeric PROTAC molecules are prepared through a convergent approach, first synthesizing two fragments separately and then coupling them to produce a fully assembled PROTAC.