Science brief: a reading aid, unvalidated by any person. Not a prediction and not advice. Public data only.

Science brief: targeted protein degradation

As of 2024-12-31. Topic mode. Literature: targeted protein degradation. 45 abstracts read, 24 claims checked, 0 papers had no abstract and were not read.

Read this first.

• Each claim was extracted by a model from one abstract. A second, separate reader then checked it against the abstracts in this pack, and a third checked that reader. Every line below carries two exact quotes that code found in the sources.
• The corpus is each lab's three most recent last-author papers at four year-ends, abstracts only. "No independent support found" means none in this corpus. It never means not replicated.
• The order is a published sort rule (scirank-v1): highest evidence tier among verified claims, then independent supports, then fewer contradictions. It is not a score and it predicts nothing.
• Evidence tier comes from the extraction's model-system field. "Randomized" is a word rule on the abstract.

Measured, once, on planted errors (an upper bound on real ones):

• One pass over the retrieved abstracts found 110 of 121 hard planted misstatements and named the paper that shows each (91%, 95% interval 85 to 96). It flagged 2 of 423 unaltered claims (false alarms).
• By type: a flipped direction 58 of 66 (88%, 81 to 94); a number swapped for another in the same abstract 35 of 37 (95%, 83 to 100); animal and human swapped 17 of 18 (too few for a rate).
• Baselines on the same claims: a read with no literature flagged 52% and could name no paper; the Lens with a string rule found 2%; fan-out over chunks found 89%, not better than one pass.
• Planted errors are an upper bound on real ones: one word or number was changed and the true paper was in the pack. No person has checked a real case. Reader and extractor are both Claude models; scoring was by code against a key.
• Supported records, the framed read and the ranking are not measured by this test.

Extraction: Measured accuracy on a fresh sample (agent readers, both must agree): output_type right 97% (92%–99%); model_system right 95% (90%–98%); scale right 97% (93%–99%); claim supported 98% (94%–99%); effect numbers supported 99% (92%–100%); limitations supported 93% (85%–97%).

Where a paper disagrees with a claim

None found in this pack.

Labs by strength of evidence

Claims and their evidence

Daohong Zhou, University of Florida

• C12 Combining gemcitabine with DT2216, a BCL-XL-specific PROTAC degrader, synergistically induces cell death and overcomes gemcitabine resistance in pancreatic cancer. Reported effect: Combination significantly inhibited tumor growth and prolonged survival versus individual agents; no numeric values stated in abstract.
  • animal; verified against its paper; no independent support found in this corpus; source: Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL–Specific Degrader DT2216 (2021-10-19, P18)
  • Own paper:
    • claim: "Combining gemcitabine with DT2216, a BCL-XL-specific PROTAC degrader, synergistically induces cell death and overcomes gemcitabine resistance in pancreatic cancer." / paper: "In vivo, the combination significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice compared with the individual agents in pancreatic cancer PDX models." — Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL–Specific Degrader DT2216 (2021-10-19, P18). Paper reports synergy in vitro and tumor growth inhibition and survival benefit in vivo. [R4102]
• C17 Lysine accessibility within a defined band region on BCL-xL determines PROTAC selectivity and potency; an ABT263-derived VHL-recruiting PROTAC degrades BCL-xL and BCL-2 with improved anti-leukemic activity.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, (2021-11-25, P11)
  • Own paper:
    • claim: "Lysine accessibility within a defined band region on BCL-xL determines PROTAC selectivity and potency" / paper: "the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation" — Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, (2021-11-25, P11). Paper states that lysine accessibility determines PROTAC selectivity and potency, with a defined band region on BCL-xL. [R4121]

Olorunseun Olatunji Ogunwobi, Cornell University

• C02 An engineered 3'UTR-derived c-MYC destabilizing construct (3'UTR MYC1-18), delivered on iron oxide nanocages, degrades the c-MYC-STAT5A/B-PD-L1 complex and inhibits metastatic triple-negative breast cancer. Reported effect: Survival was significantly prolonged; no numerical effect size stated in the abstract.
  • animal; verified against its paper; no independent support found in this corpus; source: The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer (2024-07-26, P01)
  • Own paper:
    • claim: "delivered on iron oxide nanocages, degrades the c-MYC-STAT5A/B-PD-L1 complex and inhibits metastatic triple-negative breast cancer" / paper: "complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes" — The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer (2024-07-26, P01). Same construct, delivery vehicle, complex and survival result. [R4092]
• C06 Engineered destabilizing 3'UTR ARE ERBB2 constructs delivered by iron oxide nanocages reduce ERBB2 and inhibit primary tumor growth and liver and lung metastasis in resistant NSCLC. Reported effect: 50% complete tumor lysis; 60%-80% inhibition of liver metastasis; 90% inhibition of lung metastasis with desARE3'UTRERBB2-30.
  • animal; verified against its paper; no independent support found in this corpus; source: Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 (2024-04-18, P13)
  • Own paper:
    • claim: "50% complete tumor lysis; 60%-80% inhibition of liver metastasis; 90% inhibition of lung metastasis with desARE3'UTRERBB2-30" / paper: "We achieved significant reduction of the primary tumor volume with desARE3'UTRERBB2-30, achieving 50% complete tumor lysis and inhibiting 60%-80% of liver metastasis, hepatomegaly, and 90% of lung metastasis" — Nanocage-incorporated engineered destabilized 3'UTR ARE of ERBB2 inhibits tumor growth and liver and lung metastasis in EGFR T790M osimertinib- and trastuzumab-resistant and ERBB2-expressing NSCLC via the reduction of ERBB2 (2024-04-18, P13). Construct, model and all numbers match. [R4096]

Pengda Liu, University of North Carolina at Chapel Hill

• C14 SPOP and OTUD7A are the E3 ligase and deubiquitinase controlling EWS-FLI1 protein stability; OTUD7A is a therapeutic target, and its inhibitor 7Ai reduces EWS-FLI1 levels and tumor growth.
  • animal; verified against its paper; no independent support found in this corpus; source: SPOP and OTUD7A Control EWS–FLI1 Protein Stability to Govern Ewing Sarcoma Growth (2021-06-01, P35)
  • Own paper:
    • claim: "SPOP and OTUD7A are the E3 ligase and deubiquitinase controlling EWS-FLI1 protein stability" / paper: "7Ai reduces EWS-FLI1 protein levels and decreases Ewing sarcoma growth in vitro and in a xenograft mouse model." — SPOP and OTUD7A Control EWS–FLI1 Protein Stability to Govern Ewing Sarcoma Growth (2021-06-01, P35). Paper identifies SPOP and OTUD7A as controlling EWS-FLI1 and reports 7Ai lowering EWS-FLI1 and tumor growth. [R4104]
• C05 Lenalidomide downregulates ACE2 protein abundance and thereby alleviates infection by SARS-CoV-2 spike protein conditioned pseudoviruses.
  • not stated; verified against its paper; no independent support found in this corpus; source: Lenalidomide downregulates ACE2 protein abundance to alleviate infection by SARS-CoV-2 spike protein conditioned pseudoviruses (2021-05-10, P36)
  • Own paper:
    • claim: "Lenalidomide downregulates ACE2 protein abundance" / paper: "Lenalidomide downregulates ACE2 protein abundance to alleviate infection by SARS-CoV-2 spike protein conditioned pseudoviruses" — Lenalidomide downregulates ACE2 protein abundance to alleviate infection by SARS-CoV-2 spike protein conditioned pseudoviruses (2021-05-10, P36). Paper title states the same result. [R4095]

Sarah M. Wignall, Northwestern University

• C21 Auxin-inducible degradation of degron-tagged proteins in C. elegans, with TIR1 expressed in target tissues, enables rapid auxin-mediated protein depletion via the proteasome.
  • animal; verified against its paper; no independent support found in this corpus; source: Methods for Rapid Protein Depletion in C. elegans using Auxin‐Inducible Degradation (2021-02-01, P41)
  • Own paper:
    • claim: "Auxin-inducible degradation of degron-tagged proteins in C. elegans, with TIR1 expressed in target tissues" / paper: "When the plant hormone auxin is added, it mediates an interaction between TIR1 and the degron-tagged protein of interest, which triggers ubiquitination of the protein and its rapid degradation via the proteasome." — Methods for Rapid Protein Depletion in C. elegans using Auxin‐Inducible Degradation (2021-02-01, P41). Same system, TIR1 in target tissues and rapid proteasomal degradation. [R4111]

Allen C. Gao, University of California, Davis

• C15 ARVib, a novel AR/AR-V7 degrader, degrades AR/AR-V7 via the ubiquitin-proteasome pathway through HSP70/STUB1 modulation and inhibits resistant prostate tumor growth. Reported effect: Abstract states ARVib "significantly inhibits resistant prostate tumor growth" but gives no numerical effect size.
  • animal; verified against its paper; no independent support found in this corpus; source: ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling (2021-07-16, P29)
  • Own paper:
    • claim: "degrades AR/AR-V7 via the ubiquitin-proteasome pathway through HSP70/STUB1 modulation" / paper: "Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation." — ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling (2021-07-16, P29). Same degrader, mechanism and tumor growth claim. [R4105]

Roberto Chiarle, Harvard University

• C16 FBXO11 mutations impair BCL6 degradation, and FBXO11 is a haploinsufficient oncosuppressor in B-cell lymphoma; BCL6 targeting via degraders or inhibitors partially impairs Burkitt lymphoma growth. Reported effect: FBXO11 mutations found in 23% of patients with Burkitt lymphoma; BCL6 targeting partially impaired lymphoma growth; Omomyc with BCL6 targeting increased apoptosis.
  • animal; verified against its paper; no independent support found in this corpus; source: Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma (2021-10-11, P16)
  • Own paper:
    • claim: "FBXO11 mutations impair BCL6 degradation, and FBXO11 is a haploinsufficient oncosuppressor in B-cell lymphoma" / paper: "Here, we show that FBXO11 mutations are found in 23% of patients with Burkitt lymphoma (BL)." — Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma (2021-10-11, P16). Paper matches the 23% figure, partial growth impairment and Omomyc result. [R4106]

Nathanael S. Gray, Stanford University

• C03 FPFT-2216 degrades PDE6D in addition to IKZF1, IKZF3, and CK1α, and medicinal chemistry derivatives TMX-4100 and TMX-4116 show greater selectivity for PDE6D and CK1α, respectively.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216 (2021-12-29, P21)
  • Own paper:
    • claim: "FPFT-2216 degrades PDE6D in addition to IKZF1, IKZF3, and CK1α" / paper: "FPFT-2216, a previously reported “molecular glue” compound, degrades PDE6D, in addition to IKZF1, IKZF3, and CK1α." — Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216 (2021-12-29, P21). Paper states the same degradation profile and the same derivatives. [R4093]
• C04 CDK2-targeting N-acyl-N-alkylsulfonamide (NASA) acylation probes with a CRBN recruiting ligand selectively functionalize Lys89 on purified or native CDK2, but do not induce CDK2 degradation. Reported effect: Selective functionalization of Lys89 observed; no CDK2 degradation observed, in contrast to efficient degradation by the reversible bivalent degrader.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development (2021-07-21, P33)
  • Own paper:
    • claim: "selectively functionalize Lys89 on purified or native CDK2, but do not induce CDK2 degradation" / paper: "NASA-mediated reaction resulted in selective functionalization of Lys89 on purified or native CDK2." — Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development (2021-07-21, P33). Paper reports Lys89 functionalization and no observed CDK2 degradation. [R4094]

Lindsey Ingerman James, University of North Carolina at Chapel Hill

• C18 UNC8153, a novel NSD2-targeted degrader, potently and selectively reduces cellular NSD2 protein and H3K36me2 via proteasome-dependent degradation, producing mild antiproliferative and antiadhesive effects in multiple myeloma cells. Reported effect: Mild antiproliferative effects in MM1.S cells and antiadhesive effects in KMS11 cells; no numerical effect sizes stated.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2 (2023-03-28, P07)
  • Own paper:
    • claim: "Mild antiproliferative effects in MM1.S cells and antiadhesive effects in KMS11 cells" / paper: "mild antiproliferative effects in MM1.S cells containing an activating point mutation and antiadhesive effects in KMS11 cells harboring the t(4;14) translocation" — Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2 (2023-03-28, P07). Paper reports the same mild antiproliferative and antiadhesive effects in the same cell lines. [R4122]
• C24 UNC7700, an EED-targeted PROTAC with a unique cis-cyclobutane linker, degrades PRC2 components and reduces H3K27me3 levels in DB cells. Reported effect: EED DC50 = 111 nM, Dmax = 84%; EZH2 WT/EZH2 Y641N DC50 = 275 nM, Dmax = 86%; SUZ12 Dmax = 44%; anti-proliferative EC50 = 0.79 ± 0.53 μM after 24 h in DB cells.
  • in vitro; not verified against its paper; no independent support found in this corpus; source: PROTAC Linkerology Leads to an Optimized Bivalent Chemical Degrader of Polycomb Repressive Complex 2 (PRC2) Components (2023-03-06, P10)

Weiping Tang, University of Wisconsin–Madison

• C19 Triantennary GalNAc (tri-GalNAc) conjugated to biotin, antibodies, or antibody fragments acts as an ASGPR-targeting degrader that delivers extracellular and membrane proteins to lysosomes for degradation in liver cells.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Development of Triantennary N‑Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins (2021-03-04, P28)
  • Own paper:
    • claim: "delivers extracellular and membrane proteins to lysosomes for degradation in liver cells" / paper: "We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders." — Development of Triantennary N‑Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins (2021-03-04, P28). Paper reports lysosomal delivery and degradation of extracellular targets in liver cell lines by tri-GalNAc degraders. [R4123]

Thomas J. Kodadek, University of Florida

• C07 A mammalian cell line with HaloTag fused to the proteasome via Rpn13 allows chloroalkane-linked chimeras to drive ubiquitin-independent degradation of some BET and Cdk2/7/9 targets.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Recruitment to the Proteasome Is Necessary but Not Sufficient for Chemically Induced, Ubiquitin-Independent Degradation of Native Proteins (2024-10-23, P40)
  • Own paper:
    • claim: "HaloTag fused to the proteasome via Rpn13 allows chloroalkane-linked chimeras" / paper: "We show that chimeric molecules comprised of a chloroalkane linked to a ligand for the BET family of proteins or the Cdk2/7/9 family of kinases result in ubiquitin-independent degradation of some of these target proteins." — Recruitment to the Proteasome Is Necessary but Not Sufficient for Chemically Induced, Ubiquitin-Independent Degradation of Native Proteins (2024-10-23, P40). Same cell line, ligands and ubiquitin-independent degradation of some targets. [R4097]

William G. Kaelin, Harvard University

• C20 A gain-of-signal ("up") assay can identify protein degraders; it found novel IMiD-like IKZF1 degraders and Spautin-1, which degrades IKZF1 cereblon-independently.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Targeting oncoproteins with a positive selection assay for protein degraders (2021-02-05, P45)
  • Own paper:
    • claim: "found novel IMiD-like IKZF1 degraders and Spautin-1, which degrades IKZF1 cereblon-independently." / paper: "In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner." — Targeting oncoproteins with a positive selection assay for protein degraders (2021-02-05, P45). Paper states the same screen result for IKZF1 degraders and Spautin-1. [R4124]

Zhijian Qian, University of Florida

• C22 A novel METTL3 degrader, ZW27941, designed to induce VHL-mediated proteasomal degradation of METTL3, shows anti-leukemic activity in AML and synergizes with cytarabine and venetoclax. Reported effect: Synergistic or additive effects reported with cytarabine and venetoclax; no numerical values stated in abstract.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia (2024-11-07, P17)
  • Own paper:
    • claim: "designed to induce VHL-mediated proteasomal degradation of METTL3" / paper: "Furthermore, ZW27941 demonstrated synergistic or additive effects when combined with standard AML therapeutics, such as cytarabine and venetoclax." — Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia (2024-11-07, P17). Same degrader, VHL mechanism, anti-leukemic activity and combination effects. [R4112]

Alice Y. Ting, Stanford University

• C09 A fully genetically encodable LYTAC (GELYTAC) using IGF2 in place of the glycopeptide, directed-evolved for potency, can be secreted by engineered human primary T cells to drive uptake of target proteins.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Directed evolution of genetically encoded LYTACs for cell-mediated delivery (2024-03-21, P31)
  • Own paper:
    • claim: "fully genetically encodable LYTAC (GELYTAC) using IGF2 in place of the glycopeptide" / paper: "our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells." — Directed evolution of genetically encoded LYTACs for cell-mediated delivery (2024-03-21, P31). Same construct, IGF2 swap, directed evolution and T-cell secretion. [R4099]

Michael J. Palladino, University of Pittsburgh

• C13 Genome-wide RNAi screen of quality control proteins identified 25 regulators of TPI sugarkill turnover, including co-translational quality control and ribosome factors, suggesting co-translational selection for degradation. Reported effect: 25 regulators identified from 430 proteins screened, 10 of which were novel previously undescribed Drosophila proteins.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Identification of protein quality control regulators using a Drosophila model of TPI deficiency (2021-02-16, P02)
  • Own paper:
    • claim: "25 regulators identified from 430 proteins screened, 10 of which were novel previously undescribed Drosophila proteins" / paper: "Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified." — Identification of protein quality control regulators using a Drosophila model of TPI deficiency (2021-02-16, P02). Counts and the co-translational interpretation match the paper. [R4103]

Xiaolin Cheng, The Ohio State University

• C23 Selective TBL1X PROTAC degraders, with O-linked PROTACs such as TD11 reducing TBL1X levels, may serve as chemical tools against DLBCL. Reported effect: Eight PROTACs showed strong cytotoxic activity; most O-linked PROTACs significantly reduced TBL1X levels, while N-linked PROTACs showed minimal degradation; no numeric values stated.
  • in vitro; verified against its paper; no independent support found in this corpus; source: Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders (2024-10-01, P14)
  • Own paper:
    • claim: "most O-linked PROTACs significantly reduced TBL1X levels, while N-linked PROTACs showed minimal degradation" / paper: "Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation." — Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders (2024-10-01, P14). Paper reports the same linker-dependent TBL1X degradation result. [R4125]

Andrew Tsourkas, University of Pennsylvania

• C10 An engineered bioPROTAC template complexed with cationic and ionizable lipids via electrostatic interactions enables cytosolic delivery and rapid degradation of intracellular proteins. Reported effect: Up to 95% clearance of targets within hours of treatment.
  • not stated; verified against its paper; no independent support found in this corpus; source: Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins (2024-07-10, P24)
  • Own paper:
    • claim: "complexed with cationic and ionizable lipids via electrostatic interactions" / paper: "exhibiting near-complete elimination (up to 95% clearance) of targets within hours of treatment." — Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins (2024-07-10, P24). Same bioPROTAC template and up to 95% clearance within hours. [R4100]

Eric S. Fischer, Harvard University

• C11 A bump-and-hole engineered BRD4 BD1 L94V degradation tag, with the CRBN-based heterobifunctional degrader XY-06-007, enables selective rapid protein degradation and can be combined with the dTAG system. Reported effect: DC50 of 10 nM at 6 h; no degradation of off-targets by whole proteome mass spectrometry.
  • not stated; verified against its paper; no independent support found in this corpus; source: Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based Degradation Tag (2021-07-19, P19)
  • Own paper:
    • claim: "DC50 of 10 nM at 6 h; no degradation of off-targets by whole proteome mass spectrometry" / paper: "XY-06-007 shows a half-degradation concentration (DC 50, 6 h ) of 10 nM against BRD4 BD1 L94V with no degradation of off-targets" — Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based Degradation Tag (2021-07-19, P19). Same degrader, tag, DC50 and absence of off-target degradation. [R4120]

Ophir Shalem, University of Pennsylvania

• C08 Pooled endogenous gene tagging with a ligand-binding domain combined with small-molecule-based recruitment can screen for effector proteins that induce target degradation via protein proximity.
  • not stated; verified against its paper; no independent support found in this corpus; source: Pooled endogenous protein tagging and recruitment for systematic profiling of protein function (2024-09-09, P12)
  • Own paper:
    • claim: "Pooled endogenous gene tagging with a ligand-binding domain combined with small-molecule-based recruitment" / paper: "We combine pooled endogenous gene tagging using a ligand-binding domain with generic small-molecule-based recruitment to screen for induction of protein proximity." — Pooled endogenous protein tagging and recruitment for systematic profiling of protein function (2024-09-09, P12). Paper describes the same screening approach for degradation effectors. [R4098]

Stuart H. Orkin, Harvard University

• C01 Heterologous recognition domains replacing the PRY-SPRY domain of erythroid-enriched E3 ligases TRIM10 and TRIM58 can redirect them to degrade BCL11A.
  • not stated; verified against its paper; no independent support found in this corpus; source: Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains (2024-12-13, P23)
  • Own paper:
    • claim: "replacing the PRY-SPRY domain of erythroid-enriched E3 ligases TRIM10 and TRIM58" / paper: "We established a general strategy in which heterologous recognition domains replace the PRY-SPRY domain of TRIM10 and TRIM58." — Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains (2024-12-13, P23). Paper reports the same replacement of the PRY-SPRY domain in TRIM10 and TRIM58. [R4119]

Framed read (unvalidated: one model's synthesis of the records above)

Claim that carries the most weight: C07. C07 is the one claim here that describes degradation without ubiquitin, so any reading of this pack as a single proteasome-driven degradation story depends on it being right as stated. Its only record, R4097, is from the claim's own paper and its quote says degradation of "some of these target proteins", so the scope of the claim is narrower than the claim line.

What would have to hold:

• The ubiquitin-independent result in C07 must hold beyond its own paper; R4097 is the only record and it is not independent, and no independent paper in this pack addresses it.
• The Rpn13 HaloTag cell line in C07 must be what causes the degradation; R4097 quotes the chimeric molecules and the outcome, and no record covers the Rpn13 fusion itself.
• The lipid complexation and electrostatic mechanism in C10 must hold; R4100 quotes only the clearance result, and no record covers the lipid formulation.
• The no-degradation half of C04 must hold; R4094 quotes only the Lys89 functionalization, and no record covers the absence of CDK2 degradation.
• The animal-tier efficacy statements, for example C12 (R4102) and C14 (R4104), must hold in independent hands; each rests on one non-independent record, and R4104 quotes only the 7Ai result, not the SPOP and OTUD7A assignment.

Questions a data room would have to answer:

• (C07) Which target proteins in the Rpn13 HaloTag line were not degraded by the chloroalkane chimeras, and has any group outside the originating lab reproduced degradation without ubiquitin in this line?
• (C04) What data show that the CRBN-recruiting NASA probes fail to degrade CDK2, and was the probe tested at the same concentrations and times as the reversible bivalent degrader?
• (C10) What lipid compositions and cell types were used for the bioPROTAC delivery, and how was cytosolic delivery separated from non-specific loss of target protein?
• (C14) What evidence supports SPOP as the E3 ligase and OTUD7A as the deubiquitinase for EWS-FLI1, separate from the 7Ai xenograft result, and what were the controls for 7Ai off-target effects?
• (C12) What are the dosing, toxicity and platelet findings for DT2216 combined with gemcitabine in the patient-derived xenograft models, given that the abstract gives no numeric values?
• (C05) Was the lenalidomide effect on ACE2 abundance tested with live virus or only with spike-conditioned pseudoviruses, and in which cell types?
• (C16) What data show that FBXO11 is haploinsufficient and that the loss impairs BCL6 degradation, beyond the mutation frequency in Burkitt lymphoma patients?
• (C24) Do the reported EED and EZH2 degradation values for UNC7700 hold in cell lines other than DB, and what is the partial SUZ12 degradation explained by?

Cannot say:

• Whether any claim is reproduced by another group: every record is from the claim's own paper and none is marked independent.
• Whether claims C01 to C24 hold beyond what each quote states, since several quotes cover only part of the claim line.
• How the claims rank commercially or clinically; the records contain no cost, market or patient data.
• Which labs are stronger than others; the records test claims, not labs.
• Anything about claims with no record in this pack, including C24.

What was not shown

• Claims with no checked record: C24.
• Records proposed: 32; refused by code (a quote not found, or a number of the reader's own): 8; removed by the checker: 1.
• Papers without an abstract, not read: 0.

Run record

• run: sci-2d0ce278e9; reader arm: B1R; spec: sci-0.1; rank rule: scirank-v1
• reader prompt sha256: c04daba6743bf488eaeb3427cec02860a257d2c06ef9f58cf307195206620e03; model: claude-sonnet-5-5, medium effort
• extraction: claude-haiku-5-5, prompt extract_v0.3; no human has verified it