Abstract
Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.
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Acknowledgements
We thank all members of the Fischer and Ebert labs for the discussions and input. R.P.N. is a member of the excellence cluster ImmunoSensation2 funded by the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy — EXC2151–390873048.
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The authors contributed equally to all aspects of the article.
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Competing interests
E.S.F. is a founder, member of the scientific advisory board and equity holder of Civetta Therapeutics, Proximity Therapeutics and Neomorph, Inc. (also board of directors). He is an equity holder and scientific advisory board member for Avilar Therapeutics and Photys Therapeutics, an equity holder in Lighthorse Therapeutics and a consultant to Novartis, Sanofi, EcoR1 Capital, Ajax, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Bayer, Interline and Astellas. B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. R.P.N. and J.M.T. declare no competing interests.
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Supplementary information
Glossary
- Acetylation tagging
-
(AceTAG). Acetylation tagging system in which heterobifunctional molecules composed of ligands to acetyltransferase p300/CBP are linked by binder to FKBP12F36V and can acetylate FKBP12F36V-tagged target proteins.
- Activity-based protein profiling
-
(ABPP). A proteomics-based technology that uses chemical probes, usually consisting of a reactive group (warhead), a chemical linker and a reporter group including a tag. Probes whose reactive groups react with target proteins are isolated and identified via proteomics.
- Antibody targeting chimaeras
-
(AbTACs). Recombinant bispecific antibodies that recruit E3 ligases bound to the membrane for degradation of cell-surface proteins.
- Cullin-RING E3 ubiquitin ligase
-
(CRL). Family of E3 ubiquitin ligases that contain a cullin protein (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 or CUL7). These multicomponent complexes frequently include adaptor proteins in between the substrate receptors.
- DDB1 and cullin-associated factor
-
(DCAF). Proteins associated with cullin proteins, such as substrate receptors or substrate adaptors, in CRLs.
- Dephosphorylation-targeting chimaeras
-
(DEPTACs). Heterobifunctional peptides that recruit a phosphatase to a target protein. The approach was demonstrated to dephosphorylate tau with chimaeric peptides composed of tau binding motif, linker, PP2A phosphatase binding motif and cell-penetrating sequence.
- Deubiquitinase-targeting chimaeras
-
(DUBTACs). Heterobifunctional small molecules consisting of a deubiquitinase recruiter and a target binder. A DUBTAC has been demonstrated to deubiquitinate ΔF508-CFTR by using a covalent allosteric OTUB1 recruiter linked to lumacaftor, a ΔF508-CFTR binding small molecule.
- Fragment-based ligand discovery
-
(FBLD). A ligand discovery approach that uses small chemical fragments instead of elaborated structures in an attempt to cover wider chemical spaces with fewer molecules. After initial low-affinity binding, fragments are discovered — often using chemoproteomics approaches; these fragments are elaborated (such as the addition of functional groups, atoms or other scaffolds) into larger molecules with improved binding affinity.
- Immunomodulatory imide drugs
-
(IMiDs). A group of drugs that include the small molecules thalidomide, lenalidomide and pomalidomide, known for their immunomodulatory functions. IMiDs bind CRBN and cause degradation of transcription factors including IKZF1/3.
- Lysosome-targeting chimaeras
-
(LYTACs). Antibodies modified with a lysosome-targeting ligand, such as the tri-GalNAc substrate of asialoglycoprotein receptor (ASGPR), thus enabling the internalization of the antibody bound with its protein target. LYTACs target cell surface proteins for lysosomal degradation.
- mRNA display technology
-
A display-based technique that evolves peptides or proteins that bind to a specific target. A DNA library is first synthesized with sites for T7 RNA polymerase transcription and ribosomal binding. DNA libraries are transcribed in vitro to an mRNA library and ligated to a DNA spacer attached to puromycin. The resulting library is translated in vitro to a peptide library that is covalently linked to the mRNA and selected for binding to an immobilized target. The mRNA–DNA duplex resulting from the bound peptides is sequenced and amplified with error-prone PCR to increase diversity of the mRNA library for the next iterative cycle.
- Nuclear co-activators
-
(NCOAs). A family of proteins that bind to nuclear hormone receptors to facilitate transcriptional activation. NCOAs often bind a conserved hydrophobic cleft within nuclear receptors, which allows them to engage a broad number of targets.
- Phosphate-recruiting chimaeras
-
(PhoRCs). Heterobifunctional small molecules that recruit phosphatase to a target protein. The PhoRC system was demonstrated with DDO3711, which is a bifunctional small molecule that binds phosphatase PP5 and recruits it to ASK1 via the active site inhibitor of ASK1.
- Phosphorylation inducing chimaeras
-
(PHICs). Heterobifunctional small molecules that recruit a kinase to a target protein. PHICs were demonstrated to phosphorylate BRD4 by recruitment of AMPK or PKC kinases.
- Phosphorylation-targeting chimaeras
-
(PhosTACs). Heterobifunctional small molecules that recruit phosphatase to a target protein. The PhosTAC approach was demonstrated using FKBP12F36V-tagged phosphatase and HaloTagged-target protein with a PhosTAC composed of FKBP12F36V small-molecule binder and a halo ligand.
- Regulated induced proximity targeting chimaeras
-
(RIPTACs). Bifunctional small molecules that bring into proximity two proteins, a disease-specific protein target with a pan-essential effector protein, resulting in context-specific toxicity.
- Sumolyation
-
Sumolyation is a post-translational modification that involves the attachment of SUMO proteins (SUMO1, SUMO2 or SUMO3), small ubiquitin-like peptides, to lysine residues that lead to different aspects of protein regulation and/or function. SUMO proteins are attached to targets in an analogous process to ubiquitin, via an E1, SUMO E2 and SUMO E3 ligases.
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Tsai, J.M., Nowak, R.P., Ebert, B.L. et al. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00729-9
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DOI: https://doi.org/10.1038/s41580-024-00729-9
