Induced protein degradation is an emerging drug discovery platform with the potential to reduce drug exposure requirements, counteract compensatory protein expression and target the 'undruggable proteome'.
Selective oestrogen receptor degraders (such as fulvestrant) demonstrated some of the advantages of induced protein degradation over the traditional inhibitor-based approach.
Hydrophobic tagging attempts to mimic partially unfolded proteins to induce target protein degradation, although the exact mechanism of action remains unknown.
Proteolysis-targeting chimaeras (PROTACs) are a promising platform technology that is modular, catalytic and specific for its protein target with picomolar potencies in cell culture and demonstrated activity in mouse models.
An added layer of specificity over the traditional inhibition approach can be accomplished with PROTACs by utilizing different E3 ligases and conditional recruiting ligands.
Future development of targeted protein degradation will be focused on targeting the undruggable proteome.
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
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The authors thank S. Jamie-Figueroa, T. Neklesa, K. Raina and the rest of the Crews laboratory for their helpful comments. C.M.C. gratefully acknowledges the US National Institutes of Health (NIH) for its support (R35-CA197589). A.C.L acknowledges support from the NIH (MSTP NIH/NIGMS T32GM007205). C.M.C. is founder, consultant and shareholder of Arvinas, LLC.
C.M.C. is a founder, consultant and shareholder of Arvinas, LLC. A.C.L. declares no competing interests.
- Event-driven pharmacology
A drug discovery paradigm based on identifying compounds that lead to the removal of the target protein from the system following drug binding to the target.
Pertains to molecular compounds that have a greater effect than the 1:1 activity ratio seen with a stoichiometric agent.
A bacterial dehalogenase engineered by the Promega Corporation to covalently bind to chloroalkanes that has been used primarily for protein purification and imaging-based applications.
- Erythroblastosis oncogene B3
(ERBB3). A member of the epidermal growth factor receptor (EGFR) family that has minimal kinase activity and acts primarily as a scaffold for signal transduction.
- NF-κB inhibitor-α
(IκBα). Inhibitor of NF-κB that containing a destruction motif that, when phosphorylated, is recognized by the E3 ligase substrate recognition component β-transducin repeat-containing protein.
- von Hippel–Lindau
(VHL). The substrate recognition portion of the E3 ligase complex VHL–elongin B/C–cullin 2 (VHL–ELOBC–CUL2) that mediates the transfer of ubiquitin onto hypoxia-inducible factor 1α (HIF1α).
- Poly-D-arginine tag
An arginine-containing peptide fragment based on the HIV Tat peptide that facilitates cellular uptake of proteins.
- Occupancy-driven pharmacology
A drug discovery paradigm based on identifying compounds that modulate protein function through stoichiometric drug binding and occupation of the binding site to modulate protein function.
- Bromodomain-containing protein 4
(BRD4). A member of the bromodomain and extra-terminal (BET) family that recognizes acetylated lysines of histones to modulate the epigenetic code.
- Breakpoint cluster region–Abelson tyrosine kinase
(BCR–ABL). An oncogenic fusion of BCR and ABL that can lead to chronic myeloid leukaemia.
- Rule of five
The rule of five is a widely used guideline to predict the likelihood of poor absorption or permeability characteristics for small molecules. It is based on upper limits for physicochemical properties of the compounds, including molecular mass (for which 500 Da is the cut-off).
Peptide segments recognized by the cellular quality control system that influence the degradation rate of the full-length protein.
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Lai, A., Crews, C. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16, 101–114 (2017). https://doi.org/10.1038/nrd.2016.211
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