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Review
. 2020 Apr 2;181(1):102-114.
doi: 10.1016/j.cell.2019.11.031. Epub 2020 Jan 16.

Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

George M Burslem  1 , Craig M Crews  2
Affiliations
Review

Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery

George M Burslem et al. Cell. .

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.

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Conflict of interest statement

Declaration of Interests C.M.C. is a founder, consultant, and shareholder in Arvinas, which supports research in his lab. C.M.C. is an inventor of the following patents: 9500653 (Small-Molecule Hydrophobic Tagging of Fusion Proteins and Induced Degradation of Same), 9632089 (Small-Molecule Hydrophobic Tagging of Fusion Proteins and Induced Degradation of Same), 10145848 (Small-Molecule Hydrophobic Tagging of Fusion Proteins and Induced Degradation of Same), 9938264 (Proteolysis-Targeting Chimera Compounds and Methods of Preparing and Using Same), 7041298 (Proteolysis-Targeting Chimeric Pharmaceutical), 7208157 (Proteolysis-Targeting Chimeric Pharmaceutical), and 10071164 (Estrogen-Related Receptor Alpha-Based PROTAC Compounds and Associated Methods of Use).

Figures

Figure 1 –
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 -
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 –
Figure 3 –
PROTAC Development Workflow
Figure 4 -
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.
See this image and copyright information in PMC

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References

    1. Agrawal N, Dasaradhi PVN, Mohmmed A, Malhotra P, Bhatnagar RK, and Mukherjee SK (2003). RNA Interference: Biology, Mechanism, and Applications. Microbiology and Molecular Biology Reviews 67, 657–685. - PMC - PubMed
    1. Altmann K-H, Johannes B, Kessler H, Diederich F, Krautler B, Lippard S, Liskamp R, Muller K, Nolan EM, Samori B, et al. (2009). The State of the Art of Chemical Biology. ChemBioChem 10, 16–29. - PubMed
    1. Amm I, Sommer T, and Wolf DH (2014). Protein quality control and elimination of protein waste: The role of the ubiquitin–proteasome system. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1843, 182–196. - PubMed
    1. Ardley HC, and Robinson PA (2005). E3 ubiquitin ligases. Essays In Biochemistry 41, 15–30. - PubMed
    1. Argiropoulos B, Yung E, and Humphries RK (2007). Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes & Development 21, 2845–2849. - PubMed

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