Targeted protein degradation: elements of PROTAC design

Abstract

Targeted protein degradation using Proteolysis Targeting Chimeras (PROTACs) has emerged as a novel therapeutic modality in drug discovery. PROTACs mediate the degradation of select proteins of interest (POIs) by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation by the 26S proteasome. This hijacking mechanism has been used to degrade various types of disease-relevant POIs. In this review, we aim to highlight the recent advances in targeted protein degradation and describe the challenges that need to be addressed in order to efficiently develop potent PROTACs.

Figure 1A

Mechanistic overview of PROTAC-mediated POI ubiquitination via the ubiquitination enzymatic cascade, and POI degradation via the 26S proteasome. B. Potential shortcomings of occupancy-driven paradigm of small-molecule/drug-target binding wherein sustained target engagement is limited due to: i. catalytic inhibition offers cannot potentiate non-catalytic and/or scaffolding roles of target-protein, ii. target protein overexpression, iii. competition with overexpressed native ligand for same binding site, and iv. target protein mutations potentiate small-molecule/drug binding.

Figure 2

Overview of steps for PROTAC-mediated POI degradation in a cellular context.