CoChat
Sign Up
Cited by 200Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

Chasing molecular glue degraders: screening approaches

Open access
Domostegui, Ana, Nieto-Barrado, Luis, Perez-Lopez, Carles, Mayor-Ruiz, Cristina·2022·Chemical Society Reviews
DOI 10.1039/d2cs00197g
Open this paper in CoChat — free accountOpen PDF

Abstract

By orchestrating interactions to an E3 ubiquitin ligase, molecular glue degraders have incredible therapeutic potential against otherwise “undruggable” proteins. We discuss how their discovery is evolving from serendipity to intentional strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys molecular glue degraders—monovalent small molecules that induce or stabilize E3 ligase–target protein interactions to trigger proteasomal degradation—and traces the field’s shift from serendipitous discoveries to intentional screening strategies. It categorizes target- and E3-agnostic/driven approaches and highlights examples such as IMiDs, aryl sulfonamides, cyclin K degraders, and structure-guided Helios degraders.

Key findings

  • Molecular glue degraders are monovalent, linker-less compounds that strengthen or trigger direct E3:target interactions; they often lack affinity for at least one partner, can degrade otherwise unligandable proteins, have favorable drug-like properties, show non-saturable kinetics, and are already therapeutic as approved IMiDs (thalidomide, lenalidomide, pomalidomide). The review notes >300,000 human PPIs and, for theoretical E3–target pairings, ~420,000 proteins and about 600 human E3s.
  • Serendipitous discoveries include IMiDs hijacking CRL4^CRBN to degrade IKZF1/IKZF3 and CK1α, aryl sulfonamides hijacking CRL4^DCAF15 to degrade RBM39/RBM23, and BI-3802 inducing BCL6 polymerization and SIAH1-mediated degradation.
  • Intentional strategies converged on cyclin K degraders: (R)-CR8, dCeMM2/3/4, HQ461, and NCT02 act via CDK12/13–DDB1; a 3.5 Å structure confirmed the DDB1:CR8:CDK12-CycK complex, with DDB1–CDK12-CycK basal affinity of ~50 µM strengthened ~1000-fold by the degraders. Other examples include a 350,000-compound screen yielding β-catenin degrader NRX-1532 (optimized up to 10,000-fold), Helios degraders ALV1/ALV2, VHL–CDO1 compound 4, DEL-derived FYI979, and SUMO1 degrader HB007 from 1,596 compounds.
  • Computational modeling is mostly PROTAC-oriented; MG modeling is described as more of a “blank canvas,” and accurate E3–target pair prioritization requires computationally expensive methods.

Methods

  • Narrative review; no systematic review protocol or primary experimental dataset is reported. It synthesizes published literature and some conference/unpublished disclosures.
  • The main analysis organizes MG degrader discovery into target-agnostic/E3-agnostic, target-agnostic/E3-driven, target-driven/E3-agnostic, and target-and-ligase-driven strategies, with figures summarizing chemical properties and screening approaches.
  • Examples are drawn from cited studies, including biochemical screens, cell-based phenotypic screens, DNA-encoded libraries, structure-guided design, and computational modeling.

Limitations

  • The paper states that the lack of systematic technologies to develop or even detect MG degraders has hampered broad translational efforts; the exact threshold of natural weak PPIs needed for a molecule to act as an MG remains to be determined; and computational methods are mainly PROTAC-oriented, with accurate predictions requiring computationally expensive approaches.
  • The paper notes that some strategies/examples are unpublished or presented at conferences (e.g., NIBR VHL–CDO1, DEL-derived FYI979), limiting independent verification.
  • Evident from the text: as a narrative review, it does not perform a systematic search or quantitative synthesis, and its selection of examples is illustrative rather than exhaustive.

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

Integrity signals

Registry

Crossref · 10.1039/d2cs00197g

Cites

185 of 185 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 164 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    X-ray structures of the ternary complex confirmed the MG mode of action.

    “X-ray structures of the ternary complex confirmed the MG mode of action.160”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] source

      Not checked in the free run.

  • Findingcitation

    By combining a fluorescent JQ1-based tracer with a primary BRD4 antibody and a labeled nano-secondary antibody, the authors monitored BRD4 levels.

    “By combining a fluorescent JQ1-based tracer with a primary BRD4 antibody and a labeled nano-secondary antibody, the authors were able to monitor BRD4 levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] source

      Not checked in the free run.

  • Findingcitation

    Using a small library of compounds enriched in non-IMiD-like metabolic inhibitors, the authors found that Spautin-1 induces IKZF1 destabilization in a CRBN-independent manner.

    “Indeed, using a small library of compounds enriched in (non-IMiD-like) metabolic inhibitors, the authors found that the compound Spautin-1 induces IKZF1 destabilization in a CRBN-independent manner.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] source

      Not checked in the free run.

  • Findingcitation

    Chemical screens coupled to co-treatment with BVdU allowed identification of novel IMiD-like MG degraders of IKZF1 via concomitant resistance, e.g. MI-2-61.

    “Chemical screens coupled to co-treatment with BVdU allowed them to identify novel IMiD-like MG degraders of IKZF1 via the concomitant resistance (e.g., MI-2-61) (Fig. 7 and 8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] source

      Not checked in the free run.

  • Findingcitation

    Bellail et al. found FBXO42 and CAPRIN1 as drug interactors using genome-scale CRISPR screens and HB007-based pull-down proteomics.

    “Bellail et al. found FBXO42 (a CRL1 substrate receptor) and CAPRIN1 as drug interactors, using genome-scale CRISPR screens and HB007-based pull-down proteomics.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] source

      Not checked in the free run.

  • May combine two claims. 45
  • Classified as probably not a substantial claim. 42

  • May combine two claims.

    Findingcitation

    Several small molecules, e.g. compound 4, were found to bind VHL to CDO1, prompting polyubiquitination and subsequent proteasomal degradation of CDO1.

    “Several small molecules (e.g., ''compound 4'') were found to bind VHL to CDO1, a critical regulator of cysteine metabolism, prompting polyubiquitination and subsequent proteasomal degradation of CDO1 (Fig. 7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites ‡

      Not checked in the free run.

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

    Findingcitation

    Payne et al. applied TR-FRET to profile PROTAC-induced degradation of BRD4.

    “Recently, Payne et al. applied time-resolved fluorescence resonance energy (TR-FRET) to profile PROTAC-induced degradation of BRD4.165”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The authors screened the NCI drug-like library of 1596 compounds for SUMO1 degraders and identified CPD1, which was optimized to HB007.

    “The authors screened the NCI drug-like library of 1596 compounds in search of SUMO1 degraders and identified the small-molecule hit CPD1, which was then optimized to the lead compound HB007 (Fig. 7 and 8).163”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    ALV1 induces CRBN-dependent degradation of Helios and retains Ikaros destabilization, while ALV2 has relative selectivity for Helios.

    “The former induces CRBN-dependent degradation of Helios and also retains Ikaros destabilization, while the latter has relative selectivity for Helios.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Eos (IKZF4) also encodes a histidine residue at the same position as Helios, hence ALV1 and ALV2 also induce Eos destabilization.

    “Of note, Eos (IKZF4) also encodes a histidine residue at the same position as Helios, hence ALV1 and ALV2 also induce Eos destabilization.167”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Simonetta et al. established a high-throughput biochemical screen based on fluorescence polarization and surveyed 350,000 small compounds.

    “Building on a pSer33/Ser37 phosphodegron peptide with weak binding to the E3, Simonetta et al. established a robust high-throughput biochemical screen based on fluorescence polarization and surveyed a collection of 350 000 small compounds.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] source

      Not checked in the free run.

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

    Findingcitation

    The assay was miniaturized to a 96-well plate format, enabling scalable profiling of molecules in unmodified biological systems.

    “The assay was miniaturized to a 96-well plate format, enabling the scalable profiling of molecules in unmodified biological systems.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Unlike other glue degraders, these compounds do not exhibit affinity for the E3 alone and induced dimerization is mostly based on high cooperativity of the ternary complex.

    “Unlike other glue degraders, these compounds do not exhibit any affinity for the E3 alone and the induced dimerization is mostly based on the high cooperativity of the ternary complex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Wang et al. synthesized the IMiD derivative ALV-02-146-03 and checked that it could engage CRBN.

    “First, Wang et al. synthesized the IMiD derivative ALV-02-146-03 and checked that it could engage CRBN.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] source

      Not checked in the free run.

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

    Findingcitation

    The Helios glue degrader DKY709 from Novartis is in Phase I for solid cancers, tested as monotherapy and with spartalizumab.

    “The Helios glue degrader DKY709 (Fig. 8) from Novartis is in Phase I for solid cancers (currently tested as monotherapy and in combination with spartalizumab, an anti-PD-1).16,31”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] source

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Helios degradation weakened the anergic phenotype and reduced suppressive activity of Treg cells.

    “Helios degradation weakened the anergic phenotype (T cell unresponsiveness) and reduced the suppressive activity of Treg cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] source

      Not checked in the free run.

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

    Findingnone given

    Stuart Schreiber's lab and colleagues established DOSEDO for scalable synthesis of DNA-barcoded compounds.

    “Stuart Schreiber's lab and colleagues have established DOSEDO (diversity-oriented synthesis encoded by DNA oligonucleotides) for the scalable synthesis of DNA-barcoded compounds.”
    Quote in the paperNot a substantial claim

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

    Findingreasoning

    Using BRD4 as a preselected target and VHL as a presenter, the MG degrader FYI979 was found (unpublished).

    “Using BRD4 as a preselected target and VHL as a presenter, the MG degrader FYI979 was found (unpublished).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites §

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Zaidman et al. developed PRosettaC and performed retrospective PROTAC studies that delivered near-native ternary complexes.

    “Similarly, Zaidman et al. developed the method PRosettaC and performed retrospective PRO-TAC studies that delivered near-native ternary complexes.176”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] source

      Not checked in the free run.

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

    Premisecitation

    Several PROTACs are now in clinical trials.

    “Indeed, this exciting technology is currently transitioning to the clinic, with several PROTACs now in clinical trials.16,31”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] source

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

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

    Interpretationnone given

    Targeted protein degradation has potential to modulate the abundance of proteins that are difficult to target with conventional inhibitors.

    “This strategy has garnered significant attention in the last year owing to its potential to modulate the abundance of proteins that are difficult to target with conventional inhibitors.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Due to their modular architecture, PROTACs can be easily adapted to a spectrum of targets.

    “Due to their modular architecture, PROTACs can be easily adapted to a spectrum of targets.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Most work on targeted protein degradation has focused on chemical rewiring of the ubiquitin-proteasome system, but additional approaches harnessing other protein homeostasis machinery have been described.

    “To date, most work on TPD has focused on the chemical rewiring of the ubiquitin-proteasome system (UPS), but additional approaches harnessing other protein homeostasis machinery have been described.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Suboptimal physicochemical parameters of PROTACs can be partially counterbalanced by their catalytic mode of action.

    “Such suboptimal parameters can be partially counterbalanced by the catalytic mode of action of PROTACs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Recent advances in targeted protein degradation hold promise to expand the druggable space.

    “Recent advances in this field hold the promise to expand the druggable space.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Traditional inhibitors are based on occupancy, whereas degraders are event-driven and have a catalytic mechanism of action due to dissociation after promoting target polyubiquitination.

    “Whereas traditional inhibitors are based on occupancy, degraders are event-driven and thus have a catalytic mechanism of action due to their dissociation after promoting target polyubiquitination.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    More than 300,000 protein-protein interactions occur in human cells and are involved in all physiological processes, including disease.

    “More than 300 000 protein-protein interactions (PPIs) occur in human cells and they are involved in all physiological processes, including disease. 1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

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

    Premisecitation

    Inhibition of protein-protein interactions has proved challenging but feasible.

    “The inhibition of PPIs has arguably received more attention in the past and has proved to be challenging but still feasible.2,3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] source

      Not checked in the free run.

    • cites [3] source

      Not checked in the free run.

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

    Interpretationnone given

    Targeted protein degradation strategies, including PROTACs, overcome some limitations of traditional occupancy-based therapeutics.

    “This and other pharmacological strategies of targeted protein degradation (e.g.proteolysistargeting chimeras -PROTACs) overcome some limitations of traditional occupancy-based therapeutics.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Targeted protein degradation is an important complementation and alternative to inhibitor-based therapeutics.

    “TPD has caused great excitement in drug discovery in recent years as an important complementation and alternative to inhibitor-based therapeutics.[10][11][12][13]16”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] source

      Not checked in the free run.

    • cites [11] source

      Not checked in the free run.

    • cites [12] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Most, if not all, molecular glues act on proteins that already have a basal propensity to interact with each other.

    “Recently, the Zheng lab postulated that most, if not all, MGs act on proteins that already have a basal propensity to interact with each other, thus also differentiating this pharmacology from bifunctional molecules like PROTACs.77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FK506 and rapamycin bind FKPB12, and these binary complexes induce inhibitory interactions with calcineurin and FRAP/mTOR, respectively.

    “The former two bind to FKPB12 and these binary complexes induce inhibitory interactions with calcineurin and FRAP (later mTOR, mammalian Target of Rapamycin), respectively.78,79”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] source

      Not checked in the free run.

    • cites [79] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNMDP and related small molecules induce interaction between PDE3A and SLFN12, leading to a cytotoxic effect in cancer cells with high expression of both proteins.

    “DNMDP and related small molecules induce interaction between the phosphodiesterase PDE3A and SLFN12 (Fig. 3C and 6), leading to a cytotoxic effect in cancer cells with high expression of both proteins.75,105”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] source

      Not checked in the free run.

    • cites [105] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KI-MS2-008 stabilizes Max homodimers and renders Max less capable of binding Myc.

    “KI-MS2-008 (Fig. 6), an optimized analog of one of the drug hits, stabilizes Max homodimers and thus renders Max less capable of binding Myc.107”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] source

      Not checked in the free run.

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

    Premisecitation

    The Vif protein of HIV hijacks CRL5 and binds CBF-b, leading to degradation of A3F and A3G.

    “For instance, the Vif protein of the human immunodeficiency virus (HIV) hijacks CRL5 and binds the cotranscription factor CBF-b leading to degradation of A3F and A3G, proteins that block viral replication.[95][96][97]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [95] source

      Not checked in the free run.

    • cites [96] source

      Not checked in the free run.

    • cites [97] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHP099 and ET070 correct hyperactivation of mutant SHP2 by stabilizing its closed conformation.

    “Simple synthetic compounds can also function as intramolecular glues, as shown by SHP099 110,111 and ET070 (Fig. 6), 112 which correct the hyperactivation of mutant SHP2 by stabilizing its closed conformation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] source

      Not checked in the free run.

    • cites [111] source

      Not checked in the free run.

    • cites [112] source

      Not checked in the free run.

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

    Premisecitation

    JH-RE-06 induces REV1 dimerization to block the REV1-REV7 interaction.

    “or JH-RE-06, which induces REV1 dimerization to block the REV1-REV7 interaction (Fig. 6).109”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

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

    Premisecitation

    Synstab A promotes microtubule formation by functioning as a molecular glue.

    “Synstab A is a simple synthetic compound discovered in 2001 that, by functioning as a MG, promotes microtubule formation.104”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The V protein of simian virus 5 binds the CRL4 adaptor DDB1, bringing STAT2/STAT1 heterodimers into proximity, and degradation of STAT1 diminishes interferon response.

    “The V protein of simian virus 5 (SV5 V) binds the CRL4 adaptor DDB1, bringing in proximity the host STAT2/STAT1 heterodimers.Ubiquitination and further degradation of STAT1 largely diminishes interferon response to viral infection.99,100”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [99] source

      Not checked in the free run.

    • cites [100] source

      Not checked in the free run.

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

    Premisecitation

    RO2443 prevents MDMX binding to p53 by stabilizing an inactive MDMX homodimer.

    “Additional examples are RO2443, which prevents MDMX binding to p53 by stabilizing an inactive MDMX homodimer, 108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Streptomyces-derived manumycin polyketides asukamycin and manumycin A function as covalent MG degraders that engage UBR7 and TP53.

    “These natural products seem to function as covalent MG degraders that engage UBR7 (a putative E3) and TP53.101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] source

      Not checked in the free run.

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

    Premisecitation

    CUL2 FEM1B relies on Zn2+ ions as molecular glues to selectively recruit reduced FNIP1 during reductive stress.

    “Recently reported in mammalian cells by the Rape lab, CUL2 FEM1B relies on Zn 2+ ions as ''MGs'' to selectively recruit reduced FNIP1 (and not oxidized FNIP1) during reductive stress, thereby explaining how an E3 ligase can discriminate targets based on redox state.102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Thalidomide, lenalidomide and pomalidomide are used in clinical settings, providing evidence that MG degraders are an efficacious therapeutic strategy.

    “Currently, thalidomide, lenalidomide and pomalidomide are used in a variety of clinical settings, 59 thus providing evidence that MG degraders are an efficacious therapeutic strategy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] source

      Not checked in the free run.

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

    Premisecitation

    CRLs are the largest family of E3 ubiquitin ligases.

    “CRLs are the largest family of E3 ubiquitin ligases.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] source

      Not checked in the free run.

    • cites [137] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BI-3802 does not directly glue BCL6 to the involved E3 but induces indirect dimerization between the polymerized protein and the E3.

    “BI-3802 does not directly glue BCL6 to the involved E3 but rather induces indirect ''dimerization'' between the polymerized protein and the E3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lenalidomide induces degradation of the kinase CK1a, whereas structurally similar thalidomide and pomalidomide do not.

    “Shortly after, lenalidomide (Fig. 3D) was shown to also induce the degradation of the kinase CK1a, while the structurally similar thalidomide and pomalidomide do not.50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ceapin-A7 induces neomorphic association of ATF6a in the endoplasmic reticulum with ABCD3 in the peroxisome, acting as an inter-organelle glue.

    “Ceapin-A7 induces the neomorphic association of ATF6a in the endoplasmic reticulum with ABCD3 in the peroxisome, hence acting as an inter-organelle glue.114”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RM-018 binds cyclophilin A, and this binary complex associates with active KRAS G12C and forms a covalent bond.

    “It binds cyclophilin A, and this binary complex can associate with the active state of KRAS G12C and form a covalent bond.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] source

      Not checked in the free run.

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

    Premisecitation

    CRLs orchestrate an impressive array of eukaryotic processes and their dysregulation underlies many pathologies.

    “CRLs orchestrate an impressive array of eukaryotic processes and their dysregulation underlies many pathologies.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] source

      Not checked in the free run.

    • cites [137] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several functional genomics campaigns have helped map how the repertoire of CRLs and their regulators shape degrader efficacy, outlining putative resistance mechanisms.

    “Several functional genomics campaigns in recent years have helped map how the repertoire of CLRs and their regulators shape degrader efficacy, thus also outlining putative resistance mechanisms.141-151”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [141] source

      Not checked in the free run.

    • cites [142] source

      Not checked in the free run.

    • cites [143] source

      Not checked in the free run.

    • cites [144] source

      Not checked in the free run.

    • cites [145] source

      Not checked in the free run.

    • cites [146] source

      Not checked in the free run.

    • cites [147] source

      Not checked in the free run.

    • cites [148] source

      Not checked in the free run.

    • cites [149] source

      Not checked in the free run.

    • cites [150] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If a certain affinity threshold for the ternary complex is achieved and with proper geometry, it will translate to CycK degradation.

    “If a certain affinity threshold for the ternary complex is achieved and with proper geometry, it will translate to CycK degradation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    DDB1 and CDK12-CycK have a basal affinity of about 50 mM, which is strengthened about 1000-fold in the presence of the MG degraders.

    “DDB1 and CDK12-CycK have a basal affinity of B50 mM, which is strengthened B1000 fold in the presence of the MG degraders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A 3.5 Å structure confirmed the DDB1:CR8:DK12-CycK complex and revealed a substantial protein-protein interface of about 2100 Å.

    “Extensive profiling, including a 3.5 Å structure solved by Słabicki et al., confirmed the DDB1:CR8:DK12-CycK complex and revealed a substantial protein-protein interface (B2100 Å). 153”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    CycK degraders recruit an E3 component (DDB1), which was considered unligandable, as aryl sulfonamides showed with DCAF15.

    “these compounds recruit an E3 component (DDB1), which was considered unligandable, as aryl sulfonamides showed with DCAF15.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HQ0015 is a 3-fold more potent analog of HQ461 with a DC50 of 41 nM.

    “The chemical basis for optimizing HQ461 was dissected through a structure-activity relationship study, which found a 3-fold more potent analog: HQ0015 (DC 50 : 41 nM).134”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because SUMO1 conjugation regulates ubiquitination and degradation of many substrate proteins, it is difficult to disentangle primary SUMO1 degradation and secondary events.

    “Given that SUMO1 conjugation regulates the ubiquitination and degradation of many substrate proteins, the authors argued that it is indeed difficult to disentangle the primary (SUMO1 degradation) and secondary events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    HB007 induces the interaction of CAPRIN1 with FBXO42, recruiting SUMO1 or SUMO1-conjugated proteins to the CAPRIN1-CUL1-FBXO42 ligase complex, where SUMO1 is ubiquitinated.

    “HB007 induces the interaction of CAPRIN1 with FBXO42, then recruiting SUMO1 (or SUMO1-conjugated proteins) to the CAPRIN1-CUL1-FBXO42 ligase complex, where SUMO1 is ubiquitinated.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Other assay methodologies to detect target levels have been useful for the TPD field for high-throughput and accurate measurements, e.g. ELISA or the HiBit-LgBit split nanoluciferase system.

    “Other assay methodologies to detect target levels have been very useful for the TPD field when aiming for highthroughput and accurate measurements (e.g., ELISA or the HiBit-LgBit split nanoluciferase system).164”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] source

      Not checked in the free run.

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

    Study design and conductnone given

    The assay applied in this study seems highly labor-intensive (western blotting) but proved valid to distinguish between SUMO1 and SUMO2/3 conjugation.

    “The assay applied in this study seems highly labor-intensive (western blotting), but proved to be valid to distinguish between SUMO1 and SUMO2/3 conjugation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A glutamine residue in the second zinc-finger domain enables IMiD-induced degradation, while histidine residues in Helios (IKZF2) do not.

    “The presence of a glutamine residue in their second zing-finger domain enables IMiD-induced degradation, 47 while the histidine residues in Helios (IKZF2) do not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    When mutated in cancer, this leads to b-catenin stabilization and facilitates oncogenic transcriptional programs.

    “When mutated in cancer, this leads to b-catenin stabilization and, thereby, facilitates oncogenic transcriptional programs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Helios is critical for maintaining identity and suppressive activity of Tregs, and mouse models with Helios-deficient Treg cells show enhanced antitumor immunity.

    “Helios is critical for maintaining the identity and suppressive activity of Tregs, and mouse models with Helios-deficient Treg cells have shown enhanced antitumor immunity.168”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Regulatory T cells (Tregs) maintain normal homeostasis and self-tolerance but also repress the antitumor immune response.

    “Regulatory T cells (Tregs) are a specialized subpopulation that maintains normal homeostasis and self-tolerance to immune responses, but also represses the antitumor immune response.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    These binders are identifiable by sequencing the DNA tags uniquely associated with each compound.

    “These binders are identifiable by sequencing the DNA tags uniquely associated with each compound.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Several cycles of affinity selection, typically involving an immobilized target protein, yield binders to the protein of interest from such mixtures.

    “Several cycles of affinity selection, typically involving an immobilized target protein, yield binders to the protein of interest from such mixtures.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Computer-aided drug design has helped expedite development of small-molecule inhibitors.

    “Computer-aided drug design has helped expedite the development of small-molecule inhibitors.172,173”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] source

      Not checked in the free run.

    • cites [173] source

      Not checked in the free run.

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

    Premisecitation

    DNA encoded libraries (DELs) are increasingly being adopted in drug discovery.

    “Conceptualized by Brenner and Lerner, 170 DNA encoded libraries (DELs) are increasingly being adopted in drug discovery.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] source

      Not checked in the free run.

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

    Premisenone given

    DEL technology involves generation of large mixtures of compounds through synthetic chemistry cycles that introduce diverse building blocks encoded by unique DNA tags.

    “This technology involves the generation of large mixtures of compounds through synthetic chemistry cycles that introduce diverse building blocks encoded by unique DNA tags.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    These models could highlight cavities at protein-protein interfaces; virtual drug screening combined with refinement could help find molecules that fit those cavities and enhance target-E3 affinity.

    “In principle, these models could highlight cavities at protein-protein interfaces; virtual drug screening combined with refinement techniques could help find molecules able to fit into those cavities and enhance the target-E3 affinity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    In silico protein-protein docking provides an attractive surrogate to in vitro experiments and could assist E3-target pair prioritization by predicting geometrically compatible PPIs.

    “In silico protein-protein docking provides an attractive surrogate to in vitro experiments and could, in theory, assist E3-target pair prioritization by predicting geometrically compatible PPIs.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Beyond therapeutics, degraders have proved to be powerful research tools for precise and fast perturbation of the proteome at timescales unachievable for genetic strategies.

    “Beyond therapeutics, degraders have proved to be powerful research tools for precise and fast perturbation of the proteome at timescales that are unachievable for genetic strategies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The rapidly growing literature of computational methods, mainly PROTAC-oriented, sets the grounds for modeling proximity-inducing pharmacology, including MG degraders.

    “The rapidly growing literature of computational methods, albeit mainly PROTAC-oriented, sets the grounds for modeling proximity-inducing pharmacology, including MG degraders.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    While PROTAC's warhead-linker-warhead nature contributes hints of protein-protein binding modes, MG modeling can be a blank canvas to start with.

    “While the PROTAC's warhead-linker-warhead nature contributes important hints of protein-protein binding modes, MG modeling can be a blank canvas to start with.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The current trend of in silico protocols suggests that we are a step closer to computationally assisting the design of MG degraders and PROTACs.

    “That said, the current trend of in silico protocols suggests that we are a step closer to computationally assisting the design of MG degraders and PROTACs.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Several PROTACs are in clinical trials.

    “several PROTACs are in clinical trials”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Some approved drugs are known to act as MG degraders.

    “some approved drugs are known to act as MG degraders”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Accurate predictions require computationally expensive methods such as metadynamics-based dissociation free energy, dramatically limiting the number of screenable pairs.

    “However, accurate predictions require computationally expensive methods (e.g., metadynamics-based dissociation free energy), 184 thereby dramatically limiting the number of screenable pairs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Structural hypotheses and models to determine drug-assisted target-E3 gluing are becoming more and more accurate.

    “Structural hypotheses and models to determine drug-assisted target-E3 gluing are becoming more and more accurate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The use of cellular systems helps prioritize hit matter with drug-like properties and enables interrogation of full-length proteins in their native environment.

    “The use of cellular systems helps prioritize hit matter with drug-like properties and enables the interrogation of full-length proteins in their native environment.”
    Quote in the paperNot a substantial claim
74 of 74

  • The paper relies on this without support.

    MG degraders usually have no affinity for at least one of the two proteins in isolation.

    “MG degraders usually have no affinity for at least one of the two proteins in isolation.”

  • The paper relies on this without support.

    MG degraders have non-saturable kinetics, with no hook effect due to formation of binary complexes.

    “(iii) have non-saturable kinetics (no hook effect due to formation of binary complexes);”

  • The paper relies on this without support.

    The lack of systematic technologies to develop or even detect MG degraders has hampered broad translational efforts.

    “However, the lack of systematic technologies to develop or even detect such molecules has hampered broad translational efforts.”

  • The paper relies on this without support.

    MG interactions are not saturable, differentiating MGs from bivalent inducers of proximity.

    “These interactions are not saturable, differentiating MGs from bivalent inducers of proximity.”

  • The paper relies on this without support.

    MGs are typically characterized by lack of affinity to at least one protein partner and often prompt highly cooperative PPIs.

    “MGs are typically characterized by the lack of affinity to at least one protein partner, and they often prompt highly cooperative PPIs.”

  • The paper relies on this without support.

    The discovery of synthetic MG degraders has been driven mostly by fortuity.

    “The discovery of synthetic MG degraders has been driven mostly by fortuity, as outlined above.”

  • The paper relies on this without support.

    Chemical diversification of known glue degraders has a narrow focus on particular E3s and chemical scaffolds.

    “Of course, such chemical diversification has a narrow focus on particular E3s and chemical scaffolds.”

  • The paper relies on this without support.

    VHL and CRBN are the most exploited E3s in the TPD field.

    “VHL and CRBN are the most exploited E3s in the TPD field.”

  • The paper relies on this without support.

    Examples of E3-driven target-agnostic approaches for MG degrader discovery are scarce.

    “Examples of E3-driven target-agnostic approaches for MG degrader discovery are scarce.”

  • The paper relies on this without support.

    Signal-down strategies can be confounding and are usually noisier than positive selection methods.

    “However, this kind of ''signal-down'' strategy can be confounding and it is usually noisier than positive selection methods.”

  • The paper relies on this without support.

    Most TPD-related computational efforts to date have focused on rationalizing PROTAC-induced ternary complex formation.

    “Most TPD-related computational efforts to date have focused on rationalizing PROTAC-induced ternary complex formation.”
11 of 11

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?

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.

  • CycK degraders contradict the claimed universal non-ligandability of targets

    Minor

    The paper says all the molecular glue degraders discussed target proteins otherwise deemed non-ligandable, but later says CycK degraders bind the CDK12-CycK target complex in isolation.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Geiger, 2021, Curr. Res. Chem. Biol., 100018
  2. Pearson, 1969, Lepr. Rev., 40, 111
  3. Kofink, 2022, ChemRxiv, 10.26434/chemrxiv-2022-q63s3 · DOI
  4. Dittrich, 2003, Clin. Cancer Res., 9, 5195
  5. King, 2022, bioRxiv, 10.1101/2022.05.18.492542 · DOI

Cited by

Sorted by citations

Related

Authors
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C.
Affiliations
  • Institute for Research in Biomedicine (ES)
  • IRB Barcelona – Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac, 10, 08028 Barcelona, Spain
ORCID
Venue
Chemical Society Reviews
Publisher
Royal Society of Chemistry (RSC)
Published
2022
Volume
51
Issue
13
Pages
5498-5517
ISSN
  • 0306-0012 (ISSN-L)
  • 1460-4744
DOI
10.1039/d2cs00197g
OpenAlex
W4283211795
Cited by
200
References
185
Citations by year
2026: 47 · 2025: 65 · 2024: 42 · 2023: 42 · 2022: 4
FWCI
3.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemical Society Reviews (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
Funders
Ministerio de Ciencia e Innovación (FJC2020-043715-I, PRE2020-092066)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
molecular glues, PROTACs, E3 ubiquitin ligase, protein-protein interaction, protein degradation
MeSH terms
Proteins, Ubiquitin-Protein Ligases, 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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review