Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

Abstract

New biological tools provide new techniques to probe fundamental biological processes. Here we describe the burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system. We describe the PROTAC technology and its application to drug discovery and provide examples where PROTACs have enabled novel biological insights. Furthermore, we provide a workflow for PROTAC development and use and discuss the benefits and issues associated with PROTACs. Finally, we compare PROTAC-mediated protein-level modulation with other technologies, such as RNAi and genome editing.

Figure 1 –

Schematic representation of the ubiquitin cycle and how it can be co-opted by PROTACs. Ubiquitin-E1 thioester (UBA1 Ub complex, PDB ID:3CMM). Ubiquitin-E2 Thioester (UBE2D3-UbDha Complex PDB ID: 5IFR). Ubiquitin-E2-E3-Substrate Complex (Model Composed of PDB ID:1LQB, 5N4W and 5IFR). Ubiquitin-E2-E3-PROTAC-Neosubstrate Complex (Model Composed of PDB ID:5T35, 5N4W and 5IFR). Proteasome (PDB ID: 5I4G)

Figure 2 -

Composition of a PROTAC for BRD-4. Left – Structure of VHL ligand bound to VHL (PBD ID: 6FMI). Center – PROTAC (MZ-1)-induced ternary complex between VHL and BRD-4 (PDB ID: 5T35). Right – Structure of JQ-1 bound to BRD-4 (PDB ID:3MXF)

Figure 3 –

PROTAC Development Workflow

Figure 4 -

Diagram of a typical mammalian cell denoting locations of proteins which are susceptible to PROTAC mediated degradation. Solid lines represent locations which have been targeted with PROTACs. Dashed lines represent locations which have not yet been targeted with PROTACs.