The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.
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The authors thank J. Na for helping with DDB1 and CUL5 structural analysis and K. Lu for helping search for references. J.J. acknowledges support from the US National Institutes of Health (grants R01CA218600, R01CA230854, R01CA260666, R01GM122749, R01HD088626 and P30CA196521 from) and an endowed professorship from the Icahn School of Medicine at Mount Sinai. Y.X. acknowledges support from the US National Institutes of Health (grant R01GM067113) and an endowed professorship from the University of North Carolina at Chapel Hill. B.D. acknowledges support from the Medical Scientist Training Program (training grant T32GM007280) at the Icahn School of Medicine at Mount Sinai and the US National Institutes of Health (grant 3R01CA230854-03S1).
J.J., Y.X., H.Ü.K. and M.C. are inventors named on patent applications filed by the Icahn School of Medicine at Mount Sinai and the University of North Carolina at Chapel Hill. The Jin laboratory has received research funds from Celgene Corporation, Levo Therapeutics and Cullgen, Inc. The Xiong laboratory has received research funds from Cullgen Inc. J.J. is an equity shareholder in and consultant for Cullgen Inc. Y.X. is an equity shareholder in and currently an employee of Cullgen, Inc. B.D. and K-S.P. declare no competing interests.
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- 26S proteasome
A 2.5-MDa proteolytic protein complex that controls protein homeostasis and specific cellular process in all eukaryotes.
- Immunomodulatory imide drugs
(IMiDs). A class of small molecules that have been used in the clinic to modulate the immune system via binding the E3 ligase cereblon (CRBN). IMiDs recruit neosubstrates to CRBN for ubiquitination and subsequent degradation and have often been used as E3 ligands in proteolysis-targeting chimeras (PROTACs).
- Molecular glues
Small molecules that act like adhesives to induce or stabilize protein–protein interactions between an E3 ligase and a neosubstrate, leading to degradation of the neosubstrate.
Substrates of an E3 ligase that are not recognized by the E3 ligase under physiological conditions but interact with the E3 ligase in the presence of a molecular glue.
The HECT domain, which is approximately 350 amino acids long and homologous to the E6AP carboxy terminus (HECT), contains an evolutionarily conserved cysteine residue that forms a thioester linkage with ubiquitin.
A tripartite domain of approximately 140 amino acid in length, consisting of three zinc-binding domains, RING1–IBR–RIGN2. RING1-in-between-RIGN2 (RBR) ligases combine mechanistic features of RING-type and homologous to the E6AP carboxy terminus (HECT)-type ligases by using RING1 to recognize the E2~ubiquitin complex (the tilde denotes a high-energy thioester bond) and RING2 to form the thioester intermediate with ubiquitin.
- RING finger
First identified as a novel cysteine-rich sequence motif present in the ‘really interesting new gene’ (RING1). RING fingers promote the transfer of ubiquitin directly from E2 to the substrate by locking the E2~ubiqution conjugate (the tilde denotes a high-energy thioester bond) in a closed conformation.
S-phase kinase associated protein 1 (SKP1) binds CUL1 and functions as the adaptor protein for CRL1 complexes.
- Elongin B–elongin C complex
A heterodimer that functions as the adaptor protein complex for both CRL2 and CRL5.
A domain, first identified in cyclin F, approximately 40 amino acids long that binds the adaptor protein SKP1 and functions as the substrate receptors for CRL1 complexes.
- SOCS box
An approximately 40 amino acid region originally identified in members of suppressors of cytokine signalling proteins that consists of two separate sequences, one for binding the elongin B–elongin C heterodimer (BC box) and one for binding CUL5 (CUL5 box).
- WD40 repeat
A domain defined at the primary sequence level by a Gly-His dipeptide and a Trp-Asp (WD) dipeptide separated by 20–30 residues that is commonly found in many proteins of diverse function and typically forms β-propeller structures.
- BTB domain
Also known as the POZ domain, a conserved domain of 115–130 residues that consists of five α-helices and binds the amino-terminal domain of CUL3 and functions as the substrate receptor for cullin 3-RING ligase (CRL3) complexes.
- Cooperative binding
The enhanced binding of a proteolysis-targeting chimera (PROTAC) to both the protein of interest and the E3 ligase compared with the binding of the PROTAC to the protein of interest or the E3 ligase alone.
- Unfolded protein response
A cellular stress response that is activated by high levels of misfolded or unfolded proteins in the endoplasmic reticulum. The unfolded protein response aims to decrease the amount of unfolded proteins to maintain cellular function or induce apoptosis when this cannot be achieved.
- DDB1- and CUL4-associated factor
(DCAF). A member of a family of proteins also known as DDB1-binding WD40 (DWD) proteins that bind DDB1 and function as substrate receptors for CRL4 complexes.
Damaged DNA-binding protein complex subunit 1 (DDB1) binds CUL4 and functions as an adaptor protein for cullin 4-RING ligase (CRL4) complexes.
- Degron motif
A specific molecular feature that is recognized by E3 ligases.
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Dale, B., Cheng, M., Park, KS. et al. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer 21, 638–654 (2021). https://doi.org/10.1038/s41568-021-00365-x