Abstract
Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.
Key points
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Protein degradation by the ubiquitin–proteasome system is highly regulated at multiple levels by endogenous cellular mechanisms and external stimuli.
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Pharmaceutical interventions exploit and mimic these mechanisms by reprogramming E3 ubiquitin ligases and the proteasome to enhance, reduce or alter the degradation of selected proteins.
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Proteolysis targeting chimeras use dedicated ligands that individually bind a target protein and an E3 ligase to induce their proximity, ubiquitin transfer and effective protein degradation.
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Molecular glue degraders enhance pre-existing surface complementarities between an E3 ligase and a target protein to induce the formation of a stable ternary complex, ubiquitination and degradation.
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Novel degradation strategies such as intramolecular bivalent glues or template-assisted covalent degradation tails expand the targeted protein degradation universe and blur the lines between established modalities.
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The success of targeted protein degradation paves the way for other proximity-induced modalities, such as protein delocalization or transcriptional and epigenetic rewiring.
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Acknowledgements
We thank the members of the Winter and Ciulli labs for helpful discussions during the preparation of this review article. We apologize to all colleagues in the TPD and induced-proximity community whose work we could not appropriately cite and discuss due to space limitations. CeMM and the Winter lab are supported by the Austrian Academy of Sciences. The Winter lab is further supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 851478), by team KOODAC via the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2023/100013), Institut National Du Cancer (INCa) and KiKa (Children Cancer Free Foundation), as well as by funding from the Austrian Science Fund (FWF, projects P5918723, P36746 and P7909) and the Vienna Science and Technology Fund (WWTF, project LS21-015). The Ciulli laboratory at CeTPD receives funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant 875510 (EUbOPEN project), which receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA companies and associated partners: KTH, OICR, Diamond, and McGill; and the KOODAC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2023/100013), INCa and KiKa. A.C. is deeply grateful to the many organizations that have funded or further fund current research in his laboratory, including the UK Biotechnology and Biological Sciences Research Council (BBSRC) and other UK Research Councils, the European Research Council (ERC), the European Commission and the pharmaceutical companies Almirall, Amgen, Amphista Therapeutics, Boehringer Ingelheim, GlaxoSmithKline, Eisai, Merck KGaA, Nurix Therapeutics, Ono Pharmaceuticals and Tocris-Biotechne.
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The authors contributed equally to all aspects of the article.
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A.C. is a scientific founder and shareholder of Amphista Therapeutics, a company that is developing TPD therapeutic platforms. A.C. is on the scientific advisory board of ProtOS. G.E.W. is scientific founder and shareholder of Proxygen and Solgate Therapeutics and shareholder of Cellgate Therapeutics. G.E.W. is on the Scientific Advisory Board of Proxygen and Nexo Therapeutics. The Winter laboratory has received research funding from Pfizer. The other authors declare no competing interests.
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Glossary
- Chemoproteomics
-
Mass spectrometry-based technique used to identify how small molecules interact with and/or modify proteins either in cell lysates or in the context of intact cells.
- Click chemistry
-
A subset of synthetic chemistry reactions that aim to efficiently combine two building blocks in a way that is compatible with biological systems and therefore must be insensitive to water and oxygen.
- Degrons
-
Motifs on a substrate protein that are recognized by an E3 ubiquitin ligase or substrate receptor.
- Exit vectors
-
In medicinal chemistry and drug design, exit vectors refer to the spatial orientation in which a functional group, in the case of PROTACs the linker, is attached to the ligand scaffold.
- Hook effect
-
PROTACs can independently bind to an E3 ubiquitin ligase and a target protein. Saturated binary compound:protein interactions prevent ternary complex formation, resulting in reduced activity at high compound concentrations and a hook-shaped dose–response curve.
- Microsatellite instability
-
Deficiencies in DNA mismatch repair leading to the accumulation of replication errors, especially in short repetitive DNA sequences called microsatellites. Microsatellite instability is associated with several cancer types, particularly colon cancer.
- Neddylation
-
Attaching the ubiquitin-like protein NEDD8 to a cullin results in activation of the corresponding cullin RING E3 ligase (CRL) enzyme.
- Nuclear PML bodies
-
Dynamic, membrane-less nuclear organelles composed of a promyelocytic leukaemia (PML) protein scaffold that organizes a condensate of sumoylated client proteins, involved in diverse cellular processes including stress responses and transcriptional regulation.
- Occupancy-based inhibitors
-
A pharmacology strategy that requires the continued engagement of the target by the small molecule to induce the desired pharmacological effect, for example, protein inhibition.
- Pharmacodynamic properties
-
The effect of the drug on the body.
- Pharmacokinetic properties
-
The effect of the body on the drug, including absorption, distribution, metabolism and clearance.
- Positive cooperativity
-
Occurs when the binding of two components of the ternary complex favours the binding of the third.
- Protein turnover rates
-
Proteins are degraded and resynthesized continuously at specific rates, determining their steady-state levels and cellular half-life. Some proteins are long lived (days), others are turned over within minutes.
- Sumoylation
-
Post-translational covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a target protein to regulate its stability, activity, intracellular localization or other functions.
- Synthetic lethal interaction
-
Concurrent change (mutation or degradation) in two genes or proteins, which results in cell death where the corresponding change to each individual gene or protein does not.
- Ternary complex
-
A complex formed between an E3 ubiquitin ligase, a degrader and a target protein, where the degrader is typically sandwiched between the two proteins.
- Ubiquitin
-
A small globular protein that can be covalently attached to a lysine side chain on the surface of a target protein by the activity of an E3 ubiquitin ligase.
- Ubiquitin–proteasome system
-
(UPS). Major cellular protein degradation system comprising ubiquitin as the degradation tag, E3 ligases for ubiquitin transfer and the proteasome as the degradation compartment.
- Unfolded protein response
-
Cellular stress response triggered by the accumulation of misfolded proteins in the endoplasmic reticulum. It aims to restore protein homeostasis by promoting protein folding and degradation of misfolded proteins.
- Valosin-containing protein
-
(VCP). Known as p97 in mammals, VCP is a AAA+ ATPase that extracts ubiquitinated target proteins from cellular structures, such as protein assemblies or chromatin, for subsequent proteasomal degradation.
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Hinterndorfer, M., Spiteri, V.A., Ciulli, A. et al. Targeted protein degradation for cancer therapy. Nat Rev Cancer 25, 493–516 (2025). https://doi.org/10.1038/s41568-025-00817-8
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DOI: https://doi.org/10.1038/s41568-025-00817-8
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