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Cited by 960Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Targeted protein degradation: expanding the toolbox

Schapira, Matthieu, Calabrese, Matthew F., Bullock, Alex N., Crews, Craig M.·2019·Nature Reviews Drug Discovery
DOI 10.1038/s41573-019-0047-y
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Abstract

Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.

AI snapshot

Written from the paper’s full text.

TL;DR

This Perspective reviews targeted protein degradation by PROTACs and IMiDs and argues that expanding the E3 ligase toolbox beyond the fewer than 10 currently exploited ligases is a key enabler for the field. It surveys human E3 ligase classes, expression, cancer essentiality and ligandability to identify opportunities for new degraders.

Key findings

  • Fewer than 10 of the >600 human E3 ligases have been exploited for targeted protein degradation, while about 270 of 632 or more are believed to be involved in the ubiquitin-proteasome system; broader E3 exploration could enable tissue-specific degradation and help avoid resistance.
  • Expression analysis across 81 cell and tissue types found 24 E3 ligases present in at least 90% of samples, including MDM2 in 99%; 20 E3 ligases showed tissue-selective expression, and CDC20 was essential in all cancer types tested but had low to undetected protein levels in 70% of non-cancer cells.
  • Ligandability varies by class: DCAF WDR central cavities, BTB-Kelch KEAP1 with low-nanomolar inhibitors, VHL-box KLHDC2 with a deep C-terminal degron pocket, IAP BIR domains with low-nanomolar antagonists, TRIM bromodomains with low-nanomolar ligands, and CDC20 with the low-micromolar ligand apcin.
  • PROTACs can work with moderate E3 affinity: a VHL-recruiting PROTAC with a Kd of 320 nM degraded RIPK2 with an IC50 of 1 nM in cells, but challenges include the hook effect, acquired resistance via E3 complex alterations, off-target degradation such as IMiD-based degradation of IKZF1/IKZF3, and empirical linker/E3 pairing.

Methods

  • Perspective/review article; no new primary experiments were performed.
  • Synthesizes literature and public datasets, including UniProt/Reactome E3 annotations, Human Protein Atlas proteomics across 81 cell and tissue types, DepMap CRISPR essentiality across >340 cancer cell lines, and available crystal structures and chemical ligand data.
  • Systematically classifies human E3 ligases by mechanism and substrate-binding domain, then assesses expression, cancer essentiality and ligandability qualitatively.

Limitations

  • Stated: proteomics expression data rely on the quality and selectivity of antibodies and need further validation; the expression profile did not account for RNA levels, as noted for ASB11; ligandability assessments are constrained by available structural and chemical data.
  • Stated: PROTAC discovery remains empirical, with little rationale guiding E3 ligase–target pairing, and determinants of specificity are often complex or obscure.
  • Evident: as a Perspective, the review lacks a systematic search strategy or quantitative synthesis, and many proposed E3 opportunities are based on structural inference rather than experimental validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41573-019-0047-y

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation
    § Expression of E3 ligases · p. 11

    The expression profile of the currently exploited E3 ligases is comparatively ubiquitous.

    “The expression profile of the currently exploited E3 ligases is comparatively ubiquitous, which may translate to instances of undesired effects of PROTACs recruiting these enzymes (Fig. 3b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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  • Findingcitation
    § Classification of human E3 ligases . · p. 9

    About 270 of the 632 or more human E3 ligases are currently believed to be involved in the ubiquitin-proteasome system, based on annotations from UniProt and the Reactome Pathway database.

    “Based on the annotations of E3 ligases and their binding partners available from UniProt and the Reactome Pathway database, about 270 of the 632 or more human E3 ligases are currently believed to be involved in the UPS 55 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Liu, L. et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinformatics 35, 2882–2884 (2019). source

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  • Findingcitation
    § Expression of E3 ligases · p. 10

    Based on proteomics data across 81 cell and tissue types from the Human Protein Atlas, 24 E3 ligases are present in at least 90% of cell and tissue types tested.

    “Based on proteomics data across 81 cell and tissue types available from the Human Protein Atlas 59 (see Related links), 24 E3 ligases are present in at least 90% of cell and tissue types tested (Fig. 3a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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  • Findingcitation
    § Expression of E3 ligases · p. 10

    Among the 24 ubiquitously expressed E3 ligases, ten (RBBP7, MDM2, TOPORS, TRIM35, TRIM28, FBXW7, UBE3B, PPIL2, UBE3A and RNF20) are known to be involved in the ubiquitin-proteasome system.

    “Among these, ten (RBBP7, MDM2, TOPORS, TRIM35, TRIM28, FBXW7, UBE3B, PPIL2, UBE3A and RNF20) are known to be involved in the UPS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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  • Findingcitation
    § Expression of E3 ligases · p. 10

    MDM2 is expressed in 99% of samples tested.

    “MDM2, an E3 ligase exploited by existing PROTACs, is expressed in 99% of samples tested,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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  • Classified as probably not a substantial claim. 32

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    Findingcitation
    § Expression of E3 ligases · p. 10

    The IAP proteins BIRC2 and XIAP are hijacked by current PROTACs (also known as SNIPERs) but do not reach detectable levels in more than 50% of cell and tissue types from the Human Protein Atlas.

    “The inhibitor of apoptosis (IAP) proteins BIRC2 and XIAP are hijacked by current PROTACs (also known as specific and non-genetic IAP-dependent protein erasers (SNIPERs)) but do not reach detectable levels in >50% cell and tissue types from the Human Protein Atlas (Fig. 3a),”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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    Findingcitation
    § Expression of E3 ligases · p. 11

    ASB9, a SOCS box E3 ligase, is exclusively expressed in pancreas and testis, while the F-box E3 ligase FBXL16 is specifically found in caudate and cerebral cortex.

    “For instance, ASB9, a SOCS box E3 ligase, is exclusively expressed in pancreas and testis, while the F-box E3 ligase FBXL16 is specifically found in caudate and cerebral cortex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

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    Findingcitation
    § VHL-box and SOCS-box E3 ligases . · p. 16

    ASB4 is overexpressed in adrenal glands and in adrenocortical carcinoma.

    “ASB4 is overexpressed in adrenal glands (according to the Human Protein Atlas) and in adrenocortical carcinoma (according to The Cancer Genome Atlas) 104 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Zheng, S. et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29, 723–736 (2016). source

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  • May combine two claims.

    Premisecitation
    § Progress and lessons learned · p. 6

    PROTACs can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time.

    “and can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time 23,24,25 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Olson, C. M. et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat. Chem. Biol. 14, 163–170 (2018). source

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    • cites [24] Churcher, I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J. Med. Chem. 61, 444–452 (2018). source

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    • cites [25] Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77.e3 (2018). source

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    Premisecitation
    § Progress and lessons learned · p. 7

    PROTACs and IMiDs are generally larger and more flexible than typical drug-like compounds, which can translate into poor membrane permeability and liability to efflux pumps.

    “These molecules are generally larger and more flexible than typical drug-like compounds, which can translate into poor membrane permeability and liability to efflux pumps 39,42,43 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Popow, J. et al. Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions. J. Med. Chem. 62, 2508–2520 (2019). source

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    • cites [42] Powell, C. E. et al. Chemically induced degradation of anaplastic lymphoma kinase (ALK). J. Med. Chem. 61, 4249–4255 (2018). source

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    • cites [43] McCoull, W. et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC To provide insight into small molecule targeting of BCL6. ACS Chem. Biol. 13, 3131–3141 (2018). source

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    Interpretationnone given
    § Progress and lessons learned · p. 6

    Mutations affecting PROTAC binding but not protein function should also be expected, perhaps more so when PROTACs exploit functionally neutral sites.

    “Mutations affecting PROTAC binding but not protein function should also be expected, maybe more so when PROTACs are exploiting functionally neutral sites.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Progress and lessons learned · p. 8

    Attempts to predict protein interfaces via docking simulations have been reported, but the discovery of PROTACs remains empirical at this time.

    “Attempts to predict protein interfaces via docking simulations were recently reported 46,53 , but the discovery of PROTACs remains empirical at this time.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018). source

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    • cites [53] Drummond, M. L. & Williams, C. I. In silico modeling of PROTAC-mediated ternary complexes: validation and application. J. Chem. Inf. Model. 59, 1634–1644 (2019). source

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    Premisecitation
    § DCAF E3 ligases . · p. 13

    CRBN is one of the most characterized E3 ligases for PROTAC discovery, and a crystal structure of CRBN was solved in complex with a PROTAC and the non-native substrate BRD4, where the compound and target protein bind the atypical CULT and Lon domains of the ligase, respectively.

    “The DCAF protein CRBN, which does not feature a WDR domain, is one of the most characterized E3 ligases for PROTAC discovery, and a crystal structure of CRBN was solved in complex with a PROTAC and the non-native substrate BRD4, where the compound and target protein bind the atypical CULT and Lon domains of the ligase, respectively 46 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018). source

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    Premisecitation
    § DCAF E3 ligases . · p. 13

    EED, a critical component of the polycomb repressive complex 2, behaves as a DCAF E3 ligase that recruits PRC1 for subsequent ubiquitylation of histone substrates, and nanomolar ligands now in clinical development bind the central cavity of the EED WDR domain.

    “EED, a critical component of the polycomb repressive complex 2 (PRC2), behaves as a DCAF E3 ligase that recruits PRC1 for subsequent ubiquitylation of histone substrates 68 , and nanomolar ligands now in clinical development bind the central cavity of the EED WDR domain”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Cao, Q. et al. The central role of EED in the orchestration of polycomb group complexes. Nat. Commun. 5, 3127 (2014).

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    Premisecitation
    § Progress and lessons learned · p. 8

    The target of CRBN-binding IMiDs engages in direct interaction with the CRBN-bound phthalimide group via a β-hairpin that is structurally conserved in all available complex structures, where a critically positioned glycine abuts against the phthalimide in a binding pose that would be incompatible with any other amino acid.

    “Rather, the target engages in direct interaction with the CRBN-bound phthalimide group via a β-hairpin that is structurally conserved in all available complex structures, where a critically positioned glycine abuts against the phthalimide in a binding pose that would be incompatible with any other amino acid (Fig. 2d).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018). source

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    Premisecitation
    § DCAF E3 ligases . · p. 13

    DCAF E3 ligases are a subfamily of about 60 enzymes, 52 of which contain a WDR domain.

    “DCAF E3 ligases are a subfamily of about 60 enzymes, 52 of which contain a WDR domain 64 (Fig. 4a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Lee, J. & Zhou, P. DCAFs, the missing link of the CUL4–DDB1 ubiquitin ligase. Mol. Cell 26, 775–780 (2007). source

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    Interpretationown data
    § Expression of E3 ligases · p. 10

    The low expression of BIRC2 and XIAP could be a liability for chemical genomic approaches but is an advantage for translational studies.

    “which could be a liability for chemical genomic approaches but is an advantage for translational studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Progress and lessons learned · p. 8

    A CRBN-recruiting, IMiD-based PROTAC targeting the BTK tyrosine kinase also degrades the phthalimide-binding neo-substrates IKZF1 and IKZF3, leading to a synergistic and beneficial effect on mantle cell lymphoma.

    “For example, a CRBN-recruiting, IMiD-based PROTAC targeting the BTK tyrosine kinase also degrades the phthalimide-binding neo-substrates IKFZ1 and IKFZ3, leading to a synergistic and beneficial effect on mantle cell lymphoma 40,54 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Dobrovolsky, D. et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood 133, 952–961 (2019). source

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    • cites [54] Zorba, A. et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc. Natl Acad. Sci. USA 115, E7285–E7292 (2018). source

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    Premisecitation
    § DCAF E3 ligases . · p. 13

    The crystal structure of the homologous DCAF1 in complex with VPR indicates that substrate recognition relies on the WDR domain, a doughnut-like protein-interaction module that, in the context of other proteins, has been successfully targeted by small-molecule ligands.

    “The crystal structure of the homologous DCAF1 in complex with VPR indicates that substrate recognition relies on the WDR domain, a doughnut-like proteininteraction module that, in the context of other proteins, has been successfully targeted by small-molecule ligands 67 (Fig. 4a):”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Schapira, M., Tyers, M., Torrent, M. & Arrowsmith, C. H. WD40 repeat domain proteins: a novel target class? Nat. Rev. Drug Discov. 16, 773–786 (2017). source

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    Premisecitation
    § Essentiality of E3 ligases in cancer · p. 12

    Substrate competitors with CDC20 block mitotic exit and induce tumour cell death.

    “Substrate competitors with CDC20 block mitotic exit and induce tumour cell death 62 ,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Sackton, K. L. et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514, 646–649 (2014). source

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    Interpretationreasoning
    § DCAF E3 ligases . · p. 13

    The region of DCAF15 targeted by sulfonamides was not determined, but the WDR domain, a common protein-interaction scaffold that is also the only predicted domain of the protein, is an obvious candidate.

    “The region of DCAF15 targeted by sulfonamides was not determined, but the WDR domain, a common protein-interaction scaffold that is also the only predicted domain of the protein, is an obvious candidate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Progress and lessons learned · p. 9

    Extending the repertoire of ligands to E3 ligases with a variety of structural properties as well as diverse temporal and spatial expression profiles should considerably expand the potential applications of PROTACs for chemical biology and broaden the horizon for future drug discovery efforts.

    “Extending the repertoire of ligands to E3 ligases with a variety of structural properties as well as diverse temporal and spatial expression profiles should considerably expand the potential applications of PROTACs for chemical biology and broaden the horizon for future drug discovery efforts.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 15

    VLP acts as a dominant negative protein that lacks the C-terminal VHL-box required for Elongin B/C and Cullin 2 interaction.

    “VHLlike protein (VLP), acts as a dominant negative protein that lacks the C-terminal VHL-box required for Elongin B/C and Cullin 2 interaction 97 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Qi, H. et al. Molecular cloning and characterization of the von Hippel–Lindau-like protein. Mol. Cancer Res. 2, 43–52 (2004). source

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    § VHL-box and SOCS-box E3 ligases . · p. 16

    Over 20 human SOCS-box proteins are believed to induce degradation of their substrates.

    “Over 20 of the human SOCS-box proteins are believed to induce the degradation of their substrates (Fig. 5a).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § BTB E3 ligases. · p. 14

    KCTD5 regulates GPCR signalling through ubiquitin-mediated degradation of Gβγ subunits.

    “KCTD5, which regulates GPCR signalling through ubiquitin-mediated degradation of Gβγ subunits 85,86 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Brockmann, M. et al. Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. Nature 546, 307–311 (2017). source

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    • cites [86] Dementieva, I. S. et al. Pentameric assembly of potassium channel tetramerization domain-containing protein 5. J. Mol. Biol. 387, 175–191 (2009). source

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    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 16

    Another 37 E3 ligases use a SOCS-box domain to form Elongin B/C-containing complexes with Cullin 5.

    “Another 37 E3 ligases use a SOCS-box domain to form Elongin B/C-containing complexes with Cullin 5 (ref. 100 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Linossi, E. M. & Nicholson, S. E. The SOCS box-adapting proteins for ubiquitination and proteasomal degradation. IUBMB Life 64, 316–323 (2012). source

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    Premisecitation
    § BTB E3 ligases. · p. 15

    KLHL12 can induce degradative polyubiquitylation of dishevelled.

    “KLHL12 can induce degradative polyubiquitylation of dishevelled 89”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Angers, S. et al. The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–beta-catenin pathway by targeting Dishevelled for degradation. Nat. Cell Biol. 8, 348–357 (2006). source

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    Interpretationreasoning
    § DCAF E3 ligases . · p. 13

    WDR5 and EED are not suitable for PROTAC discovery.

    “WDR5 and EED are not believed to induce proteasomal degradation and are therefore not suitable for PROTAC discovery”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: WDR5 and EED do not induce proteasomal degradation.

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    Interpretationreasoning
    § VHL-box and SOCS-box E3 ligases . · p. 15

    KLHDC2 and KLHDC3 are potentially ligandable Kelch-domain proteins.

    “These include two Kelchdomain proteins (KLHDC2 and KLHDC3) that are potentially ligandable.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning
    § VHL-box and SOCS-box E3 ligases . · p. 15

    The remaining VHL-box proteins are less characterized and, in the absence of structural information, probably less favourable for small-molecule development.

    “that are less characterized, and in the absence of structural information are probably less favourable for small-molecule development.”
    Quote in the paperNot a substantial claim

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    Premisenone given
    § BTB E3 ligases. · p. 14

    BTB-Kelch proteins form the largest subfamily within the BTB E3 class.

    “BTB-Kelch proteins form the largest subfamily within this E3 class”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § BTB E3 ligases. · p. 15

    KLHL12 can assemble with specific co-adaptors to monoubiquitylate SEC31 for collagen trafficking.

    “it can also assemble with specific co-adaptors to monoubiquitylate the COPII component SEC31 for collagen trafficking 90,91,92”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] McGourty, C. A. et al. Regulation of the CUL3 ubiquitin ligase by a calcium-dependent Co-adaptor. Cell 167, 525–538.e14 (2016). source

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    • cites [91] Scott, D. C. et al. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166, 1198–1214.e24 (2016). source

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    • cites [92] Jin, L. et al. Ubiquitin-dependent regulation of COPII coat size and function. Nature 482, 495–500 (2012). source

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    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 16

    The Cullin 5 complex is hijacked by HIV viral protein Vif.

    “The Cullin 5 complex is well known for being hijacked by the HIV viral protein Vif 101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Guo, Y. et al. Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif. Nature 505, 229–233 (2014). source

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    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 15

    VHL-box and SOCS-box proteins contain a BC box for binding Elongin B and C, and a Cullin 2 or Cullin 5 box for assembly into CRL2 or CRL5 complexes.

    “VHL-box and SOCS-box proteins contain a BC box for binding to the adaptor proteins Elongin B and C, as well as a Cullin 2 or Cullin 5 box for their assembly into specific CRL2 or CRL5 complexes, respectively 96 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Mahrour, N. et al. Characterization of Cullin-box sequences that direct recruitment of Cul2–Rbx1 and Cul5–Rbx2 modules to Elongin BC-based ubiquitin ligases. J. Biol. Chem. 283, 8005–8013 (2008). source

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    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 16

    WSB1 forms multiple ubiquitin chain types, including K27 and K29-linked ubiquitylation of LRRK2.

    “WSB1 has been reported to form multiple ubiquitin chain types, including K27 and K29-linked ubiquitylation of LRRK2 (ref. 102 )”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Nucifora, F. C. et al. Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat. Commun. 7, 11792 (2016). source

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    Interpretationreasoning
    § DCAF E3 ligases . · p. 13

    These doughnut-like domains are possibly efficient modules for PROTAC discovery.

    “and possibly for PROTAC discovery.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § DCAF E3 ligases . · p. 13

    In the apo-structure of EED, the central cavity is shallow and looks unligandable.

    “this site is shallow and looks unligandable in the apo-structure of EED”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Schapira, M., Tyers, M., Torrent, M. & Arrowsmith, C. H. WD40 repeat domain proteins: a novel target class? Nat. Rev. Drug Discov. 16, 773–786 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DCAF E3 ligases . · p. 13

    Apcin binds at the CDC20 site and inhibits ubiquitylation of D-box-containing substrates.

    “apcin, a small molecule that binds at the same CDC20 site, inhibits the ubiquitylation of D-box-containing substrates 62 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Sackton, K. L. et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514, 646–649 (2014). source

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    Interpretationreasoning
    § DCAF E3 ligases . · p. 13

    Out of the 52 DCAF E3 ligases containing a WDR domain, some are expected to be associated with the UPS and ligandable.

    “out of the 52 DCAF E3 ligases containing a WDR domain, it is expected that some are associated with the UPS and are ligandable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § BTB E3 ligases. · p. 15

    KLHL39 appears to function as an antagonist that blocks ubiquitylation and degradation of PML and DAPK1 by KLHL20.

    “the BTB-Kelch family member KLHL39 appears to function as an antagonist that blocks the ubiquitylation and degradation of PML and DAPK1 by KLHL20 (ref. 95 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Chen, H. Y. et al. KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. Oncogene 34, 5141–5151 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 41

    The RCC1 repeat is a structural module found in multiple HECT E3 ligases, structurally related to WDR and Kelch domains, with a deep central cavity that may be chemically tractable.

    “The RCC1 repeat is a structural module found in multiple HECT E3 ligases, structurally related to WDR and Kelch domains, with a deep central cavity that may be chemically tractable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § TRIM E3 ligases . · p. 20

    TRIM proteins are a family of about 73 E3 ligases that directly interact with ubiquitin-conjugated E2 proteins via a canonical RING domain.

    “TRIM proteins are a family of about 73 E3 ligases that directly interact with ubiquitinconjugated E2 proteins via a canonical RING domain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning
    § HECT E3 ligases . · p. 19

    The central cavity of RLDs is deep and probably amenable to PROTAC discovery.

    “the central cavity is deep and probably amenable to PROTAC discovery.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 39

    Small-molecule ligands can bind to the Kelch domain of KEAP1 with nanomolar affinity.

    “Small-molecule ligands can bind to the Kelch domain of KEAP1 with nanomolar affinity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § TRIM E3 ligases . · p. 20

    TRIM24 can bind an acetylated peptide of p53, leading to ubiquitylation and degradation of p53.

    “TRIM24 can bind an acetylated peptide of the tumour suppressor p53, leading to ubiquitylation and degradation of the target 130 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Allton, K. et al. Trim24 targets endogenous p53 for degradation. Proc. Natl Acad. Sci. USA 106, 11612–11616 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 39

    The recommended threshold below which a gene is considered essential is -1.

    “The recommended threshold below which a gene is considered essential is -1 (ref. 61 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § APC E3 ligases . · p. 19

    CDC20 has favourable tissue expression profile and promising chemical tractability.

    “These data position CDC20 at an interesting intersection of favourable tissue expression profile and promising chemical tractability”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Outlook · p. 21

    DNA-encoded libraries have the potential to sample vast chemical space (>10^9 compounds) in one or more closely related experiments.

    “DNA-encoded libraries (DELs), which have the potential to sample vast chemical space in the span of one or more closely related experiments (>109 compounds) 133 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Neri, D. & Lerner, R. A. DNA-encoded chemical libraries: a selection system based on endowing organic compounds with amplifiable information. Annu. Rev. Biochem. 87, 479–502 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § F-box E3 ligases. · p. 17

    Eleven FBXW E3 ligases use a WDR domain for substrate recruitment, eight of which are known to be involved in the UPS.

    “Eleven FBXW E3 ligases use a WDR domain for substrate recruitment, eight of which are known to be involved in the UPS (Fig. 5b).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 40

    The carboxy terminus of USP1 binds the Kelch domain of KLHDC2 at a polar but well-defined pocket.

    “The carboxy terminus of USP1 binds the Kelch domain of KLHDC2 at a polar but welldefined pocket.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § APC E3 ligases . · p. 19

    Apcin binds CDC20 with low-micromolar affinity and occupies the D-box binding site.

    “apcin, that binds CDC20 with low-micromolar affinity occupies the D-box binding site of the ligase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Sackton, K. L. et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514, 646–649 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § VHL-box and SOCS-box E3 ligases . · p. 17

    RAB40C has a reported link to the UPS.

    “at least one member (RAB40C) has a reported link to the UPS 112 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Yatsu, A., Shimada, H., Ohbayashi, N. & Fukuda, M. Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes. Biol. Open 4, 267–275 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § F-box E3 ligases. · p. 17

    Phosphodegrons of endogenous targets bind the central cavity of FBXW E3 ligases such as BTRC and FBXW7.

    “Phosphodegrons (phosphorylated peptides) of endogenous targets bind the central cavity of FBXW E3 ligases such as BTRC and FBXW7.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 39

    The geometries and electrostatic potentials of the Kelch and WDR domains are diverse, indicating variable ligandability.

    “The geometries and electrostatic potentials of the Kelch and WDR domains are diverse, indicating variable ligandability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 40

    SH2 domains recruit phosphodegrons and are generally too polar for the development of drug-like inhibitors.

    “SH2 domains recruit phosphodegrons and are generally too polar for the development of drug-like inhibitors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § TRIM E3 ligases . · p. 21

    GID4 features a substrate-binding domain with a deep, enclosed and ligandable pocket that recognizes the amino-terminal proline residue of protein substrates, leading to their proteasomal degradation.

    “GID4, the subunit of the GID E3 ligase complex, features a substrate-binding domain with a deep, enclosed and ligandable pocket that recognizes the amino-terminal proline residue of protein substrates, leading to their proteasomal degradation 131,132 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Dong, C. et al. Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway. Nat. Chem. Biol. 14, 466–473 (2018). source

      Not checked in the free run.

    • cites [132] Chen, S.-J., Wu, X., Wadas, B., Oh, J.-H. & Varshavsky, A. An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes. Science 355, eaal3655 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § TRIM E3 ligases . · p. 20

    A small-molecule ligand binds with low-nanomolar affinity to the bromodomain of TRIM24, and a crystal structure shows the inhibitor deeply inserted into the acetyl-lysine binding pocket.

    “a small-molecule ligand can bind with low-nanomolar affinity to the bromodomain of TRIM24, and a crystal structure shows that the inhibitor is deeply inserted into the acetyl-lysine binding pocket of the bromodomain 129”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Palmer, W. S. et al. Structure-guided design of IACS-9571, a selective high-affinity dual TRIM24–BRPF1 bromodomain inhibitor. J. Med. Chem. 59, 1440–1454 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § IAP E3 ligases. · p. 18

    Bestatin binds BIRC2 with moderate affinity and induces its auto-ubiquitylation and degradation.

    “bestatin, which binds BIRC2 with moderate affinity and induces its auto-ubiquitylation and degradation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] Okuhira, K. et al. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett. 585, 1147–1152 (2011). source

      Not checked in the free run.

    • cites [121] Sekine, K. et al. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J. Biol. Chem. 283, 8961–8968 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Outlook · p. 21

    Different E3 ligases are expressed at different times and in different tissues.

    “as different E3 ligases are expressed at different times and in different tissues”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § APC E3 ligases . · p. 19

    The APC is a large, multisubunit E3 ligase that induces exit from mitosis by targeting cyclin B and securin for proteasomal degradation.

    “The APC is a large, multisubunit E3 ligase that induces exit from mitosis by targeting cyclin B and securin for proteasomal degradation 123 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Peters, J.-M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell Biol. 7, 644–656 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § F-box E3 ligases. · p. 18

    Structural studies of FBXO44 indicate cavities at the surface of the FBA domain, but no ligand has been described so far.

    “Structural studies of FBXO44 indicate the presence of cavities at the surface of the FBA domain, but no ligand has been described so far 116 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Kumanomidou, T. et al. The structural differences between a glycoprotein specific F-box protein Fbs1 and its homologous protein FBG3. PLOS ONE 10, e0140366 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § F-box E3 ligases. · p. 17

    F-box E3 ligases are a subfamily of about 75 proteins that use a canonical F-box domain to interact with SKP1, mediating Cullin 1 binding for recruitment of E2-ubiquitin conjugates.

    “F-box E3 ligases are a subfamily of about 75 proteins that use a canonical F-box domain to interact with the adaptor protein SKP1, mediating Cullin 1 binding for recruitment of E2ubiquitin conjugates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § HECT E3 ligases . · p. 19

    Crystal structures of ITCH and NEDD4 WW domains in complex with peptide substrates reveal a shallow but hydrophobic binding site that accommodates proline-rich motifs, but with unclear ligandability.

    “The crystal structures of ITCH and NEDD4 WW domains in complex with peptide substrates reveal a shallow but hydrophobic binding site that accommodates proline-rich motifs, but with unclear ligandability 125 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Qi, S., O’Hayre, M., Gutkind, J. S. & Hurley, J. H. Structural and biochemical basis for ubiquitin ligase recruitment by arrestin-related domain-containing protein-3 (ARRDC3). J. Biol. Chem. 289, 4743–4752 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § IAP E3 ligases. · p. 18

    IAP proteins constitute a small class of five E3 ligases that bind substrate proteins via BIR domains.

    “IAP proteins constitute a small class of five E3 ligases that bind substrate proteins via their baculoviral IAP repeat (BIR) domains (Fig. 5c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 39

    The WDR domain of EED is druggable.

    “the WDR domain of EED is druggable”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Figure 2 | Structures of ternary complexes formed during targeted protein degradation. a, b | · p. 39

    Almost all DDB1-CUL4-associated factor (DCAF) E3 ligases have a WDR domain.

    “Almost all DDB1-CUL4associated factor (DCAF) E3 ligases have a WDR domain.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    E3 ligases that are essential to the survival of cancer cells can be exploited for PROTACs without unacceptable toxicity to normal cells.

    “Exploiting E3 ligases that are essential to the survival of cancer cells is a promising strategy to avoid this resistance mechanism.”

  • The paper relies on this without support.

    Protein expression levels from the Human Protein Atlas indicate functional availability of E3 ligases for PROTAC-mediated degradation.

    “PROTACs are only active if the E3 ligase they recruit is available in the cells or tissue of interest.”
    “Based on proteomics data across 81 cell and tissue types available from the Human Protein Atlas 59 (see Related links), 24 E3 ligases are present in at least 90% of cell and tissue types tested (Fig. 3a).”

  • The paper relies on this without support.

    WDR5 and EED do not induce proteasomal degradation.

    “WDR5 and EED are not believed to induce proteasomal degradation”

  • The paper relies on this without support.

    Approximately 90 of the 220 human BTB-containing proteins function as Cullin 3-dependent E3 ligases.

    “Approximately 90 of the 220 human BTB-containing proteins are thought to function as Cullin 3-dependent E3 ligases”

  • The paper relies on this without support.

    CDC20 is essential in all cancer types.

    “CDC20 is essential in all cancer types”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Compared with traditional occupancy-based inhibitors, PROTACs offer advantages in dosing precision, side effect management, drug resistance prevention, and modulation of undruggable targets.

    “Compared with traditional occupancy-based inhibitors, PROTACs offer several advantages with respect to dosing precision, side effect management, drug resistance prevention, and the modulation of ‘undruggable’ targets21,22.”

    From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [22]

    The Abstract (p. 2) describes potential advantages over occupancy-based inhibitors in dosing, side effects, drug resistance, and modulating ‘undruggable’ targets. The claim presents those potential advantages as established and specifies dosing precision and resistance prevention, which the source does not establish; Progress and lessons learned (p. 6) instead notes dosing challenges and possible acquired resistance to PROTACs. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • More than 600 human ubiquitin E3 ligases exist.

    “With more than 600 human ubiquitin E3 ligases79,80 to potentially explore”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [80]

  • More than 600 E3 ligases in the human genome fall into different classes depending on which ubiquitin ligation strategy they use.

    “the more than 600 E3 ligases in the human genome fall into different classes, depending on which ubiquitin ligation strategy they use (reviewed in refs80,108–110).”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [80]

  • Several recent reviews have analysed publicly available datasets for ligase expression in healthy and diseased states to highlight ligases with clear and distinct expression profiles.

    “several recent reviews have analysed and categorized publicly available datasets — such as GTEx, The Cancer Genome Atlas (TCGA), ProteinAtlas and others — for ligase expression in healthy and diseased states, to highlight ligases with clear and distinct expression profiles80,99,143,144.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [80]

  • The malleability of neddylated CRLs, coupled with numerous UB carrying enzyme partners, may underlie successful molecular glue or PROTAC-targeted protein degradation, while potential limits in their multivalent catalytic architectures may explain failures in such chemically-directed ubiquitylation of heterologous substrates.

    “The malleability of neddylated CRLs, coupled with numerous UB carrying enzyme partners, may underlie successful molecular glue or PROTAC-targeted protein degradation, while potential limits in their multivalent catalytic architectures may explain failures in such chemically-directed ubiquitylation of heterologous substrates45.”

    From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [45]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Compound name differs from the cited reference

    Minor

    The text calls the CRBN modulator "C-220," while the cited reference names it "CC-220."

1 of 1

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Authors
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M.
Affiliations
  • University of Toronto (CA)
  • Pfizer (United States) (US)
  • University of Oxford (GB)
  • Yale University (US)
Corresponding author
Schapira, Matthieu
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2019-10-30
Volume
18
Issue
12
Pages
949-963
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-019-0047-y
OpenAlex
W2982554531
Semantic Scholar
e0debf22cb71e620d39f15414542d197d4f114e8
Cited by
960
References
138
Citations by year
2026: 149 · 2025: 165 · 2024: 142 · 2023: 116 · 2022: 122 · 2021: 131 · 2020: 131 · 2019: 2 · 2014: 1
FWCI
8.81
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
Funders
Wellcome Trust (106169/Z/14/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
targeted protein degradation, PROTACs, E3 ubiquitin ligase, ubiquitin-proteasome system, undruggable targets, chemical biology
MeSH terms
Enzyme Inhibitors, Humans, Neoplasms, Ubiquitin-Protein Ligases, Molecular Targeted Therapy, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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