Abstract
Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.
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Acknowledgements
C.M.C. is funded by the NIH (R35CA197589) and supported by an American Cancer Research Professorship. The authors thank A. Cacace and I. Taylor for critical reading of the manuscript; M. J. Haas for providing editorial support; and the reviewers for their supportive comments during finalization of the manuscript. PROTAC is a registered trademark of Arvinas Operations, Inc.
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C.M.C. is a consultant and shareholder in Arvinas, Inc. and Halda Therapeutics, which support research in his lab. M.B. and D.R.L. are employees and shareholders of Arvinas, Inc, which is developing drug candidates in the targeted protein degradation space.
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Glossary
- Event-driven pharmacology
-
This refers to the mechanism of action of a small-molecule drug, whereby its function is transiently recruited to a target protein in a catalytic manner (for example, ubiquitylation by an E3 ligase recruited by a proteolysis-targeting chimera (PROTAC)), resulting in a pharmacological effect (degradation of the protein) that drives a phenotype. This contrasts with occupancy-driven pharmacology, whereby the function of a target protein is directly blocked by a small-molecule inhibitor.
- Therapeutic window
-
The dosage (a range of concentrations) of a drug that provides efficacious therapy and is safe (without toxic side effects).
- Scaffolding proteins
-
Proteins that may not have an enzymatic function on their own, but serve as protein–protein interaction hubs to recruit and orient signalling complexes.
- dTAG system
-
An allele-specific tagging system that uses a protein of interest (POI) fused to a FKBP12(F36V) construct that allows specific degradation of the fused POI via an FKBP12(F36V) binder linked to a cereblon (CRBN) or a von Hippel–Lindau (VHL) ligand.
- Bio-orthogonal chemistry
-
A chemical reaction that occurs inside a living organism without altering its biology.
- Rule of 5
-
A set of physicochemical property guidelines for small molecules that indicate the likelihood of a small molecule being orally bioavailable in humans. It is more of a rule of thumb than an absolute rule, and many approved drugs fall outside the rule of 5.
- Protein half-life
-
The time required for the amount or concentration of a protein to be reduced by 50% under physiological conditions. It is a measure of the propensity of a protein to be degraded by the ubiquitin–proteasome system (UPS). Proteins with short half-lives are rapidly degraded by the UPS (constantly being turned over), whereas proteins with long half-lives are more stable.
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Békés, M., Langley, D.R. & Crews, C.M. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21, 181–200 (2022). https://doi.org/10.1038/s41573-021-00371-6
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DOI: https://doi.org/10.1038/s41573-021-00371-6
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