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Cited by 126Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

Open access
He, Yonghan, Khan, Sajid, Huo, Zhiguang, Lv, Dongwen, Zhang, Xuan, Liu, Xingui, Yuan, Yaxia, Hromas, Robert +3 more·2020·Journal of Hematology & Oncology
DOI 10.1186/s13045-020-00924-zPMC PMC7384229
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Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a sub-stoichiometric manner), ability to target “undruggable” and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes PROTACs targeting oncoproteins in hematologic malignancies and proposes using human pan-tissue single-cell RNA sequencing to identify cell type- or tumor-selective E3 ligases for safer degraders. It catalogs preclinical PROTACs with potent in vitro and in vivo activity but notes that none has yet entered clinical trials for hematologic malignancies.

Key findings

  • PROTACs act catalytically and sub-stoichiometrically, can target “undruggable” and mutant proteins, and may overcome resistance to small molecule inhibitors; Table 1 compares PROTACs with SMIs, monoclonal antibodies, and therapeutic nucleic acids.
  • Representative degraders in Table 2 include DT2216 (VHL, Bcl-xL), which degraded Bcl-xL in MOLT-4 cells with DC50 63 nM and Dmax 90.8%, and once-weekly dosing completely inhibited MOLT-4 xenografts; SIAIS178 (VHL, BCR-ABL) degraded BCR-ABL in K562 cells with DC50 8.5 nM and EC50 24 nM and dose-dependently inhibited K562 xenograft growth; SD-36 (CRBN, STAT3) achieved Dmax 90% in MOLM-16 cells and induced complete tumor regression in MOLM-16 xenografts at 100 mg/kg weekly or 50 mg/kg twice weekly for 4 weeks; MD-224 (CRBN, MDM2) had EC50 1.5 nM in RS4-11 cells and achieved complete tumor regression at 25 mg/kg daily 5 days/week for 2 weeks or 50 mg/kg every other day for 3 weeks.
  • Using Human Cell Landscape scRNA-seq data from 37 adult tissues and 315 cell types, the authors identified transcripts for 574 of more than 600 putative E3 ligases; they highlight BIRC3 as highly expressed in several hematologic malignant cells and SYVN1 as plasmocyte-selective, proposing them as candidates for cell-selective PROTACs.
  • Safety concerns include complete and prolonged target depletion, loss of scaffolding functions, off-target degradation (e.g., CRBN neosubstrates SALL4, IKZF1, IKZF3), the Hook effect, and limitations of VHL- and CRBN-based PROTACs; no PROTAC has entered clinical trials for hematologic malignancies.

Methods

  • Narrative review that systematically summarizes reported PROTACs against targets implicated in hematologic malignancies and discusses safety and clinical translation.
  • Literature review plus analysis of human pan-tissue scRNA-seq data (Human Cell Landscape) from 37 adult tissues and 315 cell types; 574 E3 ligase transcripts were identified from more than 600 putative E3 ligases.
  • scRNA-seq processing used Seurat with quality filtering (unique transcript counts <300 or >2500, >20% mitochondrial counts removed), global-scaling normalization, log-transformation, mean expression per cell type, and heatmap visualization; Table 2 compiles DC50, EC50, Dmax, and in vivo efficacy data.

Limitations

  • The paper states that PROTACs may cause greater on-target toxicity than SMIs due to complete target depletion, loss of scaffolding functions, and prolonged target depletion; it also states off-target degradation, Hook effect, E3 ligase-related drawbacks, and potential VHL/CRBN tumor suppressor issues.
  • The paper states that no PROTAC has entered clinical trials for hematologic malignancies, so the reviewed hematologic malignancy PROTAC data are preclinical.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and the proposed cell type-selective E3 ligase strategy is based on descriptive scRNA-seq analysis without experimental validation; the paper also notes that identifying appropriate E3 ligase ligands remains critical and challenging.

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

Integrity signals

Registry

Crossref · 10.1186/s13045-020-00924-z

Cites

243 of 243 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 216 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The ability of these PROTACs to degrade mutant forms of BTK was not evaluated.

    “However, the ability of these PROTACs to degrade mutant forms of BTK was not evaluated [115].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Huang H-T, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. source

      Not checked in the free run.

  • Findingown data

    The expression of SYVN1 is low in other cell types in the hematopoietic system.

    “In addition, the expression of SYVN1 is low in other cell types in the hematopoietic system (Fig. 3).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Transcripts for 574 from more than 600 putative E3 ligases were successfully identified in the HCL data.

    “Finally, transcripts for 574 from more than 600 putative E3 ligases were successfully identified in the HCL data [213].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLoS One. 2008;3:e1487.

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  • Findingown data

    There is an obvious cluster of cell-type non-specific E3 ligases consisting of ZFAND5, WSB1, and TNFAIP3, because they are expressed across different cell types in many tissues.

    “There is an obvious cluster of cell-type non-specific E3 ligases consisting of ZFAND5, WSB1, and TNFAIP3, because they are expressed across different cell types in many tissues.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among the top 57 highly expressed E3 ligases in hematopoietic cells, RBX1, ZFAND5, WSB1, ANAPC11, SOCS3, KRT8, RNF181, LGALS3BP, BIRC3, and IVNS1ABP are the top 10 ubiquitously expressed E3 ligases in various hematopoietic cells.

    “Among them, RBX1, ZFAND5, WSB1, ANAPC11, SOCS3, KRT8, RNF181, LGALS3BP, BIRC3, and IVNS1ABP are the top 10 ubiquitously expressed E3 ligases in various hematopoietic cells”
    Quote in the paperNot a substantial claim
  • May combine two claims. 79
  • Classified as probably not a substantial claim. 20

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    Findingown data

    SYVN1 is lowly expressed in proliferating B cells and moderately expressed in some differentiated B cells (centrocytes), but highly expressed in plasmocytes, suggesting its expression is upregulated during B cell differentiation.

    “SYVN1 is lowly expressed in proliferating B cells and moderately expressed in some differentiated B cells, i.e., centrocytes, but highly expressed in plasmocytes (Fig. 3), suggesting that its expression is upregulated during B cell differentiation.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    There are many other cell type-specific E3 ligases identified at the single-cell level, such as KCTD12 in blood dendritic cells, and TRIM22 in blood plasmacytoid dendritic cells.

    “Besides the E3 ligases discussed above, there are many other cell type-specific E3 ligases identified at the single-cell level (Fig. 3), such as KCTD12 in blood dendritic cells, and TRIM22 in blood plasmacytoid dendritic cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    KRT8 is highly expressed in cells in gastrointestinal tract, prostate, and pancreas, but lowly expressed in cells of brain and hematopoietic system.

    “KRT8 is highly expressed in cells in gastrointestinal tract, prostate, and pancreas, but lowly expressed in cells of brain and hematopoietic system (Additional file 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    BCR-ABL is an oncogenic fusion protein implicated in the development of chronic myelogenous leukemia.

    “BCR-ABL is an oncogenic fusion protein implicated in the development of chronic myelogenous leukemia (CML) [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33–44. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DT2216 is more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.

    “DT2216, a representative PROTAC that hijacks the VHL E3 ligase to achieve tissue/cell-selective degradation of Bcl-xL, was found to be more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source

      Not checked in the free run.

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    Premisecitation

    Mcl-1 is upregulated in various hematologic malignancies such as multiple myeloma and AML and in some solid tumors such as hepatocellular carcinoma and NSCLC.

    “Mcl-1 is upregulated in various hematologic malignancies (e.g., multiple myeloma (MM) and AML) and some solid tumors (e.g., hepatocellular carcinoma and NSCLC) [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Fletcher S. MCL-1 inhibitors - where are we now (2019)? Expert Opin Ther Pat. 2019;29:909–19. source

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    Premisecitation

    McCoull et al. developed Bcl-6 PROTACs that could degrade Bcl-6 in a number of cells but did not improve antiproliferative activity over Bcl-6 inhibitors in DLBCL cells.

    “Although the PROTAC molecules could degrade Bcl-6 in a number of cells, they did not improve antiproliferative activity over Bcl-6 inhibitors in DLBCL cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] McCoull W, Cheung T, Anderson E, Barton P, Burgess J, Byth K, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6. ACS Chem Biol. 2018;13:3131–41. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PROTACs can overcome drug resistance resulting from mutations of a protein of interest or compensatory increase in protein of interest induced by small molecule inhibitors.

    “Third, PROTACs can be used to overcome drug resistance resulting from mutations of a POI or compensatory increase in POI induced by SMIs [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    PROTACs produce longer and stronger biological effects than small molecule inhibitors on a target.

    “Because of this unique mechanism of action (MOA), PROTACs produce longer and stronger biological effects than SMIs on a target”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bcl-6 inhibitors have suffered from low potency due to the challenge of disrupting protein-protein interactions and thus have limited clinical application.

    “However, due to the challenge of disrupting PPI, these Bcl-6 inhibitors have suffered from low potency [72] and thus have limited clinical application.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Sameshima T, Yamamoto T, Sano O, Sogabe S, Igaki S, Sakamoto K, et al. Discovery of an irreversible and cell-active BCL6 inhibitor selectively targeting Cys53 located at the protein-protein interaction interface. Biochemistry. 2018;57:1369–79. source

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  • May combine two claims.

    Interpretationreasoning

    PROTACs have a better chance for faster clinical development against a broader range of targets in multiple tumor types than monoclonal antibodies and therapeutic nucleic acids.

    “Considering these limitations of using monoclonal antibodies and TNAs, PROTACs have a better chance for faster clinical development against a broader range of targets in multiple tumor types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DT2216 potently degraded Bcl-xL protein and inhibited MOLT-4 T-ALL in vitro and in vivo.

    “Moreover, DT2216 potently degraded Bcl-xL protein and inhibited MOLT-4 T-ALL in vitro and in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BI-3802, by degrading Bcl-6 via the ubiquitin proteasome system, displayed stronger de-repression of target genes than Bcl-6 inhibitors and demonstrated antiproliferative effects in several DLBCL cell lines.

    “By degrading Bcl-6 via the UPS, BI-3802 displayed stronger de-repression of target genes than Bcl-6 inhibitors and demonstrated antiproliferative effects in several DLBCL cell lines [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Kerres N, Steurer S, Schlager S, Bader G, Berger H, Caligiuri M, et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 2017;20:2860–75. source

      Not checked in the free run.

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    Premisecitation

    SIAIS178 potently degraded BCR-ABL protein with a DC50 of 8.5 nM and inhibited the proliferation of K562 cells with an EC50 of 24 nM, and further efficiently inhibited tumor growth and induced BCR-ABL degradation in K562 xenografts.

    “SIAIS178 potently degraded BCR-ABL protein (DC50 = 8.5 nM) and inhibited the proliferation of K562 cells (EC50 = 24 nM), and further efficiently inhibited tumor growth and induced BCR-ABL degradation in K562 xenografts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Zhao Q, Ren C, Liu L, Chen J, Shao Y, Sun N, et al. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. J Med Chem. 2019;62:9281–98. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bcl-6 is broadly expressed in many lymphomas and plays a significant role in lymphomagenesis.

    “It is broadly expressed in many lymphomas and plays a significant role in lymphomagenesis by being involved in the formation of germinal centers (GCs) during the humoral immune response [66–69].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [66] Cardenas MG, Oswald E, Yu W, Xue F, MacKerell AD, Melnick AM. The expanding role of the BCL6 oncoprotein as a cancer therapeutic target. Clin Cancer Res. 2017;23:885–93. source

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    • cites [67] Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997;276:589–92. source

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    • cites [68] Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med. 1997;186:439–48. source

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    • cites [69] Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-Centre formation and Th2-type inflammation. Nat Genet. 1997;16:161–70. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bcl-xL degraders recruiting CRBN or IAPs showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases.

    “These Bcl-xL degraders showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [60] He Y, Zhang X, Chang J, Kim H-N, Zhang P, Wang Y, et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat Commun. 2020;11:1996. source

      Not checked in the free run.

    • cites [61] Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem. 2020;199:112397. source

      Not checked in the free run.

    • cites [62] Zhang X, Thummuri D, Liu X, Hu W, Zhang P, Khan S, et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur J Med Chem. 2020;192:112186. source

      Not checked in the free run.

    • cites [63] Zhang X, Thummuri D, He Y, Liu X, Zhang P, Zhou D, et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL, 55. Chem Commun (Camb). 2019:14765–8. source

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  • May combine two claims.

    Premisecitation

    Tyrosine kinase inhibitors need to be administered continuously for life to treat CML patients likely due to the scaffolding functions of BCR-ABL that activate compensatory signaling pathways to promote the survival of leukemic stem cells.

    “However, TKIs need to be administered continuously for life to treat CML patients likely due to the scaffolding functions of BCR-ABL that activate compensatory signaling pathways to promote the survival of leukemic stem cells (LSCs) [76, 77].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] Ichim CV. Kinase-independent mechanisms of resistance of leukemia stem cells to tyrosine kinase inhibitors. Stem Cells Transl Med. 2014;3:405–15. source

      Not checked in the free run.

    • cites [77] Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119:1501–10. source

      Not checked in the free run.

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    Premisecitation

    Mutations in FLT-3 gene are found in patients with ALL (1-3%), myelodysplasia (5-10%), and AML (15-35%).

    “Mutations in the FLT-3 gene have been found in patients with ALL (1–3%), myelodysplasia (5–10%), and AML (15–35%), making it one of the most frequently mutated genes in hematologic malignancies [128].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–65. source

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  • May combine two claims.

    Premiseown data

    YX-2-107 degrades CDK6 selectively in Ph-like and MLL-rearranged cell lines and inhibits their proliferation.

    “YX-2-107, a CRBN-recruiting PROTAC, degraded CDK6 selectively in Ph-like and MLL-rearranged cell lines, and inhibited their proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    P13I efficiently degrades both wild-type and C418S BTK with DC50 values of 10 nM and 28 nM, respectively.

    “Rao’s group reported a BTK degrader, named P13I, which efficiently degraded both wild-type and C418S BTK with DC50 values of 10 nM and 28 nM, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018;28:779–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TD-428 possesses high specificity and lacks the Hook effect.

    “TD-428 possesses two unique properties: high specificity and lacking the Hook effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Kim SA, Go A, Jo S-H, Park SJ, Jeon YU, Kim JE, et al. A novel cereblon modulator for targeted protein degradation. Eur J Med Chem. 2019;166:65–74. source

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  • May combine two claims.

    Premisecitation

    MT-802, but not ibrutinib, reduces activated-BTK levels in patient-derived CLL cells harboring the C481S mutation.

    “MT-802, but not ibrutinib, was found to reduce activated-BTK levels in patient-derived CLL cells harboring the C481S mutation [116].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, et al. Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57:3564–75. source

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    Premisecitation

    QCA570 is the most potent BET PROTAC, displaying picomolar potency against human acute leukemia cell lines in vitro and in vivo.

    “QCA570 is the most potent BET PROTAC that displays picomolar potency against human acute leukemia cell lines in vitro and in vivo [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Qin C, Hu Y, Zhou B, Fernandez-Salas E, Yang C-Y, Liu L, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J Med Chem. 2018;61:6685–704. source

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    Premisecitation

    VHL-based PROTACs derived from I-BET726 selectively induce BRD3/4 degradation without effect on BRD2, but possess anti-proliferation effect against AML cells.

    “only selectively induce BRD3/4 degradation without any effect on BRD2, but still possess the anti-proliferation effect against AML cells [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Chan K-H, Zengerle M, Testa A, Ciulli A. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain and extra-terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J Med Chem. 2018;61:504–13. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some on-target toxicities of small molecule inhibitors and PROTACs.

    “These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BSJ-03-123 selectively degrades CDK6 but not CDK4 in AML cell lines because it forms a ternary complex with CDK6 and CRBN but not with CDK4 and CRBN.

    “BSJ-03-123, a CRBN-based CDK6 degrader, was reported to selectively degrade CDK6 but not CDK4 in AML cell lines because it can form a ternary complex with CDK6 and CRBN but not with CDK4 and CRBN [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Brand M, Jiang B, Bauer S, Donovan KA, Liang Y, Wang ES, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol. 2019;26:300–306.e9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARV-825 and ARV-771 displayed potent in vitro and in vivo efficacies against AML, post-myeloproliferative neoplasm secondary AML, multiple myeloma, mantle cell lymphoma, and DLBCL.

    “Later, ARV-825 and ARV-771 were tested widely and displayed potent in vitro and in vivo efficacies against AML [104, 105], post-myeloproliferative neoplasm secondary AML [106, 107], MM [108], mantle cell lymphoma (MCL) [8], and DLBCL [109].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [104] Mill CP, Fiskus W, DiNardo CD, Qian Y, Raina K, Rajapakshe K, et al. RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1. Blood. 2019;134:59–73. source

      Not checked in the free run.

    • cites [105] Piya S, Mu H, Bhattacharya S, Lorenzi PL, Davis RE, McQueen T, et al. BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment. J Clin Invest. 2019;129:1878–94. source

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    • cites [106] Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31:1951–61. source

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    • cites [107] Saenz DT, Fiskus W, Mill CP, Perera D, Manshouri T, Lara BH, et al. Mechanistic basis and efficacy of targeting the β-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors. Blood. 2020;135:1255–69. source

      Not checked in the free run.

    • cites [108] Zhang X, Lee HC, Shirazi F, Baladandayuthapani V, Lin H, Kuiatse I, et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia. 2018;32:2224–39. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTK is involved in constitutively active BCR signaling in CLL, DLBCL, and MCL, and is an important therapeutic target in these malignancies.

    “Bruton’s tyrosine kinase (BTK) is involved in constitutively active B cell receptor (BCR) signaling in various B cell malignancies CLL, DLBCL, and MCL, and thus, is an important therapeutic target in these malignancies [112].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123:1207–13. source

      Not checked in the free run.

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    Premisecitation

    BETd-260 rapidly degrades BRD2/3/4 and inhibits growth of RS4-11 B-ALL cells in vitro and in a mouse xenograft model.

    “BETd-260 exerted high potency to rapidly degrade BRD2/3/4 and inhibit the growth of RS4-11 B cell acute lymphoblastic leukemia (B-ALL) cells in vitro and in a mouse xenograft model [92].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, et al. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J Med Chem. 2018;61:462–81. source

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    Premisecitation

    DD-04-015 efficiently and selectively degrades BTK and produces similar antiproliferative activity as RN486 in BTK-dependent TMD8 DLBCL cells.

    “The RN486-based degrader, named DD-04-015, efficiently and selectively degraded BTK and produced a similar antiproliferative activity as RN486 in BTK-dependent TMD8 DLBCL cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Huang H-T, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A1874 degrades BRD4, stabilizes p53, and exhibits high anti-proliferative effect in several tumor cell lines including BL and myeloid leukemia.

    “A1874), which not only degrades BRD4, but also stabilizes p53, and exhibited high anti-proliferative effect in several tumor cell lines including BL and myeloid leukemia [95].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 2019;79:251–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term dosing or high concentrations associated with BET inhibitor treatment leads to obvious BRD4 protein accumulation and inefficient c-MYC suppression.

    “In addition, long-term dosing or high concentrations associated with BETi treatment also leads to obvious BRD4 protein accumulation and inefficient c-MYC suppression [85].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol. 2015;22:755–63. source

      Not checked in the free run.

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

    Premisecitation

    Wu et al. proposed that HDAC6-IKZFs dual degraders would achieve enhanced anti-myeloma activity based on synergistic effect of HDAC6 inhibitors and IMiDs.

    “Wu et al. proposed that HDAC6-IKZFs dual degraders would achieve an enhanced anti-myeloma activity based on the synergistic effect of HDAC6 inhibitors and immunomodulatory imide drugs (IMiDs) [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Wu H, Yang K, Zhang Z, Leisten ED, Li Z, Xie H, et al. Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J Med Chem. 2019;62:7042–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A CRBN-recruiting PROTAC based on a promiscuous kinase inhibitor failed to significantly degrade FLT-3, likely due to poor cell permeability.

    “In an early study, using a CRBN-recruiting PROTAC based on a promiscuous kinase inhibitor to target multiple kinases failed to significantly degrade FLT-3, likely due to its poor cell permeability [115].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Huang H-T, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both the FLT-3 PROTAC and inhibitor were ineffective against K562 CML cells, suggesting that the antitumor effect of the FLT-3 PROTAC on different FLT-3 ITD mutated cells is cell-dependent.

    “In addition, both the FLT-3 PROTAC and inhibitor were ineffective against other types of hematologic malignancies, such as K562 CML cells, suggesting that the antitumor effect of the FLT-3 PROTAC on different FLT-3 ITD mutated cells is cell-dependent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Burslem GM, Song J, Chen X, Hines J, Crews CM. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J Am Chem Soc. 2018;140:16428–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MD-224 can only inhibit growth of leukemia cells carrying wild-type P53 but not those with P53 mutants.

    “As expected, MD-224 can only inhibit the growth of leukemia cells carrying the wild-type P53 but not those with P53 mutants [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem. 2019;62:448–66. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDM2 SMIs including nutlins exhibit good activities against various solid and hematologic malignancies, but can cause hematopoietic suppression and gastrointestinal toxicity.

    “Several MDM2 SMIs including nutlins (nutlin 1, nutlin 2, nutlin 3) and their derivatives have been developed and exhibit good activities against various solid and hematologic malignancies, but can also cause hematopoietic suppression and gastrointestinal toxicity [144].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017;10:133. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EZH2 acts as core catalytic subunit of PRC2, and EED and SUZ12 subunits are indispensable for EZH2 catalytic activity.

    “EZH2 acts as the core catalytic subunit of PRC2, and EED and SUZ12 subunits are indispensable for EZH2 catalytic activity [151].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of MDM2 is often observed in various human cancers and can contribute to tumorigenesis.

    “Overexpression of MDM2 has been often observed in various human cancers and can contribute to tumorigenesis [142, 143].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A. 1998;95:15608–12. source

      Not checked in the free run.

    • cites [143] Teoh G, Urashima M, Ogata A, Chauhan D, DeCaprio JA, Treon SP, et al. MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells. Blood. 1997;90:1982–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The degradation effect of this PROTAC was more significant on HDAC1-2 in comparison to HDAC3, probably due to HDAC binding preference of the warhead.

    “The degradation effect of this PROTAC was more significant on HDAC1-2 in comparison to HDAC3, which can probably be attributed to the HDAC binding preference of the warhead.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Smalley JP, Adams GE, Millard CJ, Song Y, Norris JKS, Schwabe JWR, et al. PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes, Chem Commun (Camb). 2020;56:4476–9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    HDAC6 seems to be very sensitive to PROTAC-mediated degradation, probably because of its dominant cytoplasmic localization.

    “HDAC6 seems to be very sensitive to PROTAC-mediated degradation, probably because of its dominant cytoplasmic localization, whereas most other isoforms are localized in the nucleus [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Boyault C, Sadoul K, Pabion M, Khochbin S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene. 2007;26:5468–76. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most approved HDAC inhibitors have limited isoform selectivity and none have achieved clinical success for treating solid tumors as a single agent, probably due to inability to achieve high concentrations in solid tumor tissues.

    “Most of the approved drugs have limited isoform selectivity and none of the drug candidates have achieved clinical success for treating solid tumors as a single agent, which is probably due to their inability to achieve high concentrations in solid tumor tissues.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Guha M. HDAC inhibitors still need a home run, despite recent approval. Nat Rev Drug Discov. 2015;14:225–6. source

      Not checked in the free run.

    • cites [134] Gryder BE, Sodji QH, Oyelere AK. Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med Chem. 2012;4:505–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDM2 is an E3 ubiquitin ligase that acts as a powerful inhibitor of tumor suppressor P53.

    “MDM2 is a known E3 ubiquitin ligase that acts as a powerful inhibitor of the tumor suppressor P53 [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Kruse J-P, Gu W. Modes of p53 regulation. Cell. 2009;137:609–22. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The in vitro anti-proliferative activity of the FLT-3 PROTAC varies among AML cells compared to the FLT-3 inhibitor used to develop the PROTAC; it is significantly better against MV4-11 and wild-type MOLM-14, but less potent in OCI-AML3, likely due to extent of kinase engagement/selectivity.

    “However, the in vitro anti-proliferative activity of the FLT-3 PROTAC varies among AML cells compared to the FLT-3 inhibitor that was used to develop the PROTAC. For example, the PROTAC exerted a significantly better activity against MV4-11 and wild-type MOLM-14 AML cells, but was less potent in OCI-AML3 cells, than the FLT-3 inhibitor, which is likely attributed to the extent of kinase engagement”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Burslem GM, Song J, Chen X, Hines J, Crews CM. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J Am Chem Soc. 2018;140:16428–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HBL-4 is a CRBN-based BRD4/PLK1 dual degrader that is more potent than its parental inhibitor BI2536.

    “Mu et al. reported a CRBN-based BRD4/PLK1 dual degrader, HBL-4, which is more potent than its parental inhibitor BI2536 [145].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Mu X, Bai L, Xu Y, Wang J, Lu H. Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells. Biochem Biophys Res Commun. 2020;521:833–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Achieving complete and sustained inhibition of FLT-3 ITD signaling to maintain effective clinical response requires a high dose of inhibitors, which leads to off-target toxicities.

    “Achieving a complete and sustained inhibition of FLT-3 ITD signaling to maintain effective clinical response requires a high dose of inhibitors, which leads to off-target toxicities [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97:683–94. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDM2 inhibitor can lead to a significant compensatory increase in MDM2 expression, which can lead to rapid degradation of p53 upon clearance of the MDM2.

    “In addition, MDM2 inhibitor can lead to a significant compensatory increase in MDM2 expression, which can lead rapid degradation of p53 upon clearance of the MDM2 [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem. 2019;62:448–66. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Converting an HDACi into an isoform-selective HDAC PROTAC can achieve improved potency and reduced off-target toxicity.

    “By converting an HDACi into an isoform-selective HDAC PROTAC, it is possible to achieve improved potency and reduced off-target toxicity as reported recently [11, 135–138].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [11] Wu H, Yang K, Zhang Z, Leisten ED, Li Z, Xie H, et al. Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J Med Chem. 2019;62:7042–57. source

      Not checked in the free run.

    • cites [135] Yang K, Wu H, Zhang Z, Leisten ED, Nie X, Liu B, et al. Development of selective histone deacetylase 6 (HDAC6) degraders recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. ACS Med Chem Lett. 2020;11:575–81. source

      Not checked in the free run.

    • cites [136] Yang K, Song Y, Xie H, Wu H, Wu Y-T, Leisten ED, et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg Med Chem Lett. 2018;28:2493–7. source

      Not checked in the free run.

    • cites [137] Yang H, Lv W, He M, Deng H, Li H, Wu W, et al. Plasticity in designing PROTACs for selective and potent degradation of HDAC6. Chem Commun (Camb). 2019;55:14848–51. source

      Not checked in the free run.

    • cites [138] An Z, Lv W, Su S, Wu W, Rao Y. Developing potent PROTACs tools for selective degradation of HDAC6 protein. Protein Cell. 2019;10:606–9. source

      Not checked in the free run.

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

    Interpretationreasoning

    The oncogenic CALR mutant protein could be an excellent PROTAC target to treat MPN patients with CALR mutations.

    “The oncogenic CALR mutant protein could be an excellent PROTAC target to treat MPN patients with CALR mutations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SMARCA2/4 bromodomain inhibitors have failed to inhibit tumor cell growth because the ATPase domain but not the bromodomain is essential for tumor cell growth.

    “However, such inhibitors have failed to inhibit tumor cell growth [48] because the ATPase domain but not the bromodomain is essential for tumor cell growth [169].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15:672–80. source

      Not checked in the free run.

    • cites [169] Vangamudi B, Paul TA, Shah PK, Kost-Alimova M, Nottebaum L, Shi X, et al. The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res. 2015;75:3865–78. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several SMIs that block dimerization of STAT3 have reached clinical development but exhibited very limited clinical activity.

    “Several SMIs that block the dimerization of STAT3 have reached the clinical development stage, but only exhibited very limited clinical activity [173].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CALR mutations are mutually exclusive with JAK2 or MPL mutations in MPNs, suggesting common oncogenic pathways.

    “CALR mutations are mutually exclusive with JAK2 or MPL mutations in MPNs, suggesting common oncogenic pathways.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [188] Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405. source

      Not checked in the free run.

    • cites [189] Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90. source

      Not checked in the free run.

    • cites [190] Broséus J, Park J-H, Carillo S, Hermouet S, Girodon F. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124:3964–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPM1c+ acts as a dominant negative mutant for NPM1 function and has a gain-of-function role in pathogenesis of AML phenotype.

    “NPM1c+ acts as a dominant negative mutant for NPM1 function and has a gain-of-function role in pathogenesis of the AML phenotype [196, 197].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [196] Bolli N, Nicoletti I, De Marco MF, Bigerna B, Pucciarini A, Mannucci R, et al. Born to be exported: COOH-terminal nuclear export signals of different strength ensure cytoplasmic accumulation of nucleophosmin leukemic mutants. Cancer Res. 2007;67:6230–7. source

      Not checked in the free run.

    • cites [197] Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP, et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood. 2005;106:899–902. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    dBRD9 efficiently degrades BRD9 and exerts a 10-100-fold increase in antiproliferative activity than corresponding inhibitor against MOLM-13 and other AML cell lines.

    “Brander’s group reported a selective degrader of BRD9, named dBRD9, which efficiently degraded BRD9 and exerted a 10–100-fold increase in antiproliferative activity than the corresponding inhibitor against MOLM-13 and other AML cell lines [180].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Remillard D, Buckley DL, Paulk J, Brien GL, Sonnett M, Seo H-S, et al. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands. Angew Chem Int Ed Engl. 2017;56:5738–43. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Allosteric SMIs targeting SMARCA2/4 ATPase domain are orally bioavailable with in vivo antitumor activity.

    “Meanwhile, SMIs that target the allosteric binding site of the SMARCA2/4 ATPase domain and are orally bioavailable with in vivo antitumor activity have been reported [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Papillon JPN, Nakajima K, Adair CD, Hempel J, Jouk AO, Karki RG, et al. Discovery of orally active inhibitors of brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J Med Chem. 2018;61:10155–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SD-36 has desirable PK/PD properties, is well tolerated, and achieves complete and long-lasting tumor regression in mice xenografted with AML and ALCL cell lines.

    “Further, SD-36 had desirable PK/pharmacodynamic (PD) properties, was well tolerated and achieved complete and long-lasting tumor regression in mice xenografted with AML and ALCL cell lines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PROTAC2 selectively degrades EED, EZH2, and SUZ12, and reduces proliferation of EZH-dependent tumor cells Karpas422.

    “The most potent compound named PROTAC2 developed by Bloecher’s group selectively degraded EED, EZH2, and SUZ12, and reduced the proliferation of EZH-dependent tumor cells Karpas422 [161].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Hsu JH-R, Rasmusson T, Robinson J, Pachl F, Read J, Kawatkar S, et al. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem Biol. 2020;27:41–46.e17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UNC6852 selectively degrades EED, EZH2, and SUZ12, and potently inhibits proliferation of DLBCL cell lines with wild-type and Y641N mutant EZH2.

    “The most potent compounds named UNC6852 developed by James’ group also selectively degraded EED, EZH2, and SUZ12, and potently inhibited the proliferation of DLBCL cell lines with a wild-type and Y641N mutant EZH2 [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Potjewyd F, Turner A-MW, Beri J, Rectenwald JM, Norris-Drouin JL, Cholensky SH, et al. Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader. Cell Chem Biol. 2020;27:47–56.e15. source

      Not checked in the free run.

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

    Premisecitation

    More than 20% of human cancers bear mutations in genes encoding mSWI/SNF subunits.

    “Among the four distinct families of CRCs (SWI/SNF, ISWI, CHD, INO80), SWI/SNF complexes are the most implicated in diseases with more than 20% of human cancers bearing mutations in the genes encoding mammalian SWI/SNF (mSWI/SNF) subunits [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] St Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev. 2017;42:56–67. source

      Not checked in the free run.

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

    Interpretationreasoning

    The development of a PROTAC specifically targeting NPM1c+ could be a superb strategy.

    “The development of a PROTAC specifically targeting NPM1c+ could be a superb strategy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aberrant activation of STAT3 is associated with many human malignancies because STAT3 regulates numerous genes involved in tumorigenesis, progression, and drug resistance.

    “Aberrant activation of STAT3 is associated with many human malignancies [172–174], because STAT3 regulates numerous genes involved in tumorigenesis, progression, and drug resistance, and thus it has become an attractive cancer target [172].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [172] Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105. source

      Not checked in the free run.

    • cites [173] Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48. source

      Not checked in the free run.

    • cites [174] Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT2 PROTAC selectively induces SIRT2 degradation in HeLa cells and leads to more pronounced acetylation of microtubule network than corresponding inhibitor.

    “Schiedel et al. reported a PROTAC against sirtuin 2 (SIRT2). This PROTAC selectively induced SIRT2 degradation in HeLa cells and led to more pronounced acetylation of the microtubule network than the corresponding inhibitor [177].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Schiedel M, Herp D, Hammelmann S, Swyter S, Lehotzky A, Robaa D, et al. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals). J Med Chem. 2018;61:482–91. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACBI1 potently induced SMARCA2/4 and PBRM1 degradation in AML cell line and inhibited cell growth in multiple cancer cell lines.

    “ACBI1 potently induced SMARCA2/4 and PBRM1 degradation in the AML cell line, and inhibited cell growth in multiple cancer cell lines [48].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15:672–80. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although SD-36 binds to other STAT proteins such as STAT1 and STAT4, it only degrades STAT3.

    “Interestingly, although SD-36 also binds to other STAT proteins, such as STAT1 and STAT4, it only degrades STAT3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CALR mutations have been shown to be pathogenic and serve as a disease-initiating event to favor expansion of megakaryocytic lineage by specific activation of thrombopoietin receptor and uncontrolled activation of JAK2/STAT pathway.

    “CALR mutations has been shown to be pathogenic and serve as a disease-initiating event to favor the expansion of the megakaryocytic lineage by specific activation of the thrombopoietin receptor and uncontrolled activation of the JAK2/STAT pathway [191, 192].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [191] Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127:1317–24. source

      Not checked in the free run.

    • cites [192] Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MS1943 effectively degrades EZH2 and selectively kills EZH2-dependent TNBC cells, whereas EZH2 inhibitors are ineffective in blocking proliferation of TNBC cells.

    “MS1943 could effectively degrade EZH2 and selectively kill EZH2-dependent TNBC cells, whereas EZH2 inhibitors are ineffective in blocking the proliferation of TNBC cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Ma A, Stratikopoulos E, Park K-S, Wei J, Martin TC, Yang X, et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020;16:214–22. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    PROTACs targeting TRIM24, RIPK2, and JAK family enzymes may have potential to treat certain types of hematologic malignancies but require further studies.

    “In addition, PROTACs targeting tripartite motif-containing protein 24 (TRIM24), receptor-interacting protein kinase 2 (RIPK2), and the Janus kinase family enzymes for degradation may also have the potential to be used to treat certain types of hematologic malignancies but require further studies [185–187].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [185] Gechijian LN, Buckley DL, Lawlor MA, Reyes JM, Paulk J, Ott CJ, et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat Chem Biol. 2018;14:405–12. source

      Not checked in the free run.

    • cites [186] Mares A, Miah AH, Smith IED, Rackham M, Thawani AR, Cryan J, et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun Biol. 2020;3:140. source

      Not checked in the free run.

    • cites [187] Shah RR, Redmond JM, Mihut A, Menon M, Evans JP, Murphy JA, et al. Hi-JAK-ing the ubiquitin system: the design and physicochemical optimisation of JAK PROTACs. Bioorg Med Chem. 2020;28:115326. source

      Not checked in the free run.

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

    Interpretationnone given

    Degradation of SMARCA2/4 and PBRM1 subunits may disrupt integrity of BAF and PBAF complexes, resulting in dissociation of other subunits.

    “Degradation of SMARCA2/4 and PBRM1 subunits may disrupt the integrity of the BAF and PBAF complexes, resulting in the dissociation of other subunits.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Oncofusion proteins could be ideal PROTAC targets since they are alien to human cells and side effects would be easier to manage.

    “Theoretically, these oncofusion proteins could be ideal PROTAC targets, since they are “alien” to human cells and the side effects would be easier to manage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PROTACs targeting AR and ER have advanced to the clinic and preliminary results reveal that AR PROTAC ARV-110 appears clinically effective in a patient with metastatic castration-resistant prostate cancer.

    “It is encouraging that the PROTACs targeting AR and ER have advanced to the clinic and the preliminary results from these clinical studies reveal that the AR PROTAC ARV-110 appears clinically effective in a patient with metastatic castration-resistant prostate cancer (https://ir.arvinas.com/node/7666/pdf).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites https://ir.arvinas.com/node/7666/pdf

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromosomal translocations promote development of hematologic malignancies either through formation of oncogenic fusion protein or through oncogene activation by a stronger promoter or enhancer.

    “It is well established that chromosomal translocations promote the development of hematologic malignancies either through the formation of oncogenic fusion protein or through oncogene activation by a stronger promoter or enhancer [200, 201].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [200] Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233–45. source

      Not checked in the free run.

    • cites [201] Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008;359:722–34. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PROTACs might produce greater on-target toxicities than SMIs because SMIs rarely inhibit functions of targets completely, while PROTACs can almost entirely deplete their targets.

    “Although PROTACs can be more potent than SMIs against a POI, they might produce greater on-target toxicities than SMIs for several reasons. First, SMIs rarely inhibit the functions of their targets completely, while PROTACs can almost entirely deplete their targets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These binary complexes can potentially recruit off-targets and lead to their degradation and off-target toxicities.

    “These binary complexes can potentially recruit off-targets and lead to their degradation and off-target toxicities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only a few PROTACs are tumor-selective to avoid normal tissue toxicity, including platelet sparing Bcl-xL PROTACs reported by us recently by taking advantage of E3 ligases that are barely expressed in platelets.

    “Although numerous PROTACs have been generated in the past few years, only a few of them are tumor-selective to avoid normal tissue toxicity, including platelet sparing Bcl-xL PROTACs reported by us recently by taking advantage of the E3 ligases that are barely expressed in platelets [4, 60–63].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. source

      Not checked in the free run.

    • cites [60] He Y, Zhang X, Chang J, Kim H-N, Zhang P, Wang Y, et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat Commun. 2020;11:1996. source

      Not checked in the free run.

    • cites [61] Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem. 2020;199:112397. source

      Not checked in the free run.

    • cites [62] Zhang X, Thummuri D, Liu X, Hu W, Zhang P, Khan S, et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur J Med Chem. 2020;192:112186. source

      Not checked in the free run.

    • cites [63] Zhang X, Thummuri D, He Y, Liu X, Zhang P, Zhou D, et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL, 55. Chem Commun (Camb). 2019:14765–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High concentrations of PROTACs produce the Hook effect, which may lead to formation of binary complexes of PROTACs and E3 ligases.

    “However, high concentrations of PROTACs produce the “Hook effect,” which may lead to the formation of binary complexes of PROTACs and E3 ligases [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Pettersson M, Crews CM. PROteolysis targeting chimeras (PROTACs)—past, present and future. Drug Discov Today Technol. 2019;31:15–27. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRBN-based PROTACs can recruit neo-substrates such as SALL4, IKZF1, and IKZF3 to CRBN to induce their degradation, leading to adverse effects including teratogenic effect and cardiovascular, hepatic, and neuronal toxicities.

    “A well-characterized example of off-target activities of PROTACs are CRBN-based PROTACs because CRBN ligands, including thalidomide, pomalidomide, and lenalidomide, used for the CRBN-targeted PROTACs can recruit several neo-substrates such as SALL4, IKZF1, and IKZF3 to CRBN to induce their degradation [207, 208]. This can lead to some adverse effects including teratogenic effect and cardiovascular”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [207] Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane radial ray syndrome. Elife. 2018;7. source

      Not checked in the free run.

    • cites [208] Sievers QL, Petzold G, Bunker RD, Renneville A, Słabicki M, Liddicoat BJ, et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science. 2018;362. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Oncofusion proteins are often specific for subtype of hematologic malignancies, which also have potential value for PROTAC development in terms of E3 ligase selections.

    “The oncofusion proteins are often specific for subtype of hematologic malignancies, which also have potential value for PROTAC development in terms of E3 ligase selections, e.g., there are four most prevalent oncofusion proteins in AML: PML-RARα, AML1-ETO, CBFβ-MYH11, and MLL-fusions, while ETV6-RUNX1 and TCF3-PBX1 fusions are common in B-cell ALL [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Rowley JD. Chromosomal translocations: revisited yet again. Blood. 2008;112:2183–9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    SMIs may cause transient inhibition of a protein function while PROTACs induce prolonged depletion of the target protein due to their unique MOA.

    “Third, SMIs may cause a transient inhibition of a protein function while PROTACs induce prolonged depletion of the target protein due to their unique MOA.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    These findings are in agreement with Crews' recent suggestion that developing tumor-specific/selective PROTACs has potential to reduce on-target toxicities of PROTACs.

    “These findings are in agreement with Crews’ recent suggestion that developing tumor-specific/selective PROTACs has the potential to reduce the on-target toxicities of PROTACs [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18:949–63. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    VHL E3 ligase is essential for ubiquitination and degradation of HIF1a; if VHL is overly engaged by a PROTAC, it can potentially inhibit degradation of HIF1a to promote tumorigenesis.

    “Similarly, the VHL E3 ligase is essential for the ubiquitination and degradation of hypoxia-inducible factor-1 alpha (HIF1a) [209], a TF that regulates many genes necessary for tumor growth. If VHL is overly engaged by a PROTAC, it can potentially inhibit the degradation of HIF1a to promote tumorigenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTK is important for B cell development and can promote the development of B cell lymphoma.

    “An example is BTK, that is important for B cell development and can promote the development of B cell lymphoma [118].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Sun Y, Ding N, Song Y, Yang Z, Liu W, Zhu J, et al. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia. 2019;33:2105–10. source

      Not checked in the free run.

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

    Interpretationnone given

    The most challenging step for such PROTAC development will be screening for relatively specific ligands for oncofusion proteins.

    “The most challenging step for such PROTAC development will be the screening for relative specific ligands for such oncofusion proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Some POIs have both enzymatic and scaffold functions; PROTACs can completely deplete the protein, resulting in loss of both enzymatic activity and scaffolding function, which can potentially cause undesirable consequences.

    “Second, some POIs have both enzymatic and scaffold functions. The latter may be important for normal cell functions. In this case, in contrast to SMIs which only inhibit enzymatic function, PROTACs can completely deplete the protein, resulting in the loss of both enzymatic activity and scaffolding function, which can potentially cause some undesirable consequences.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The available crystal structures for some oncofusion proteins will aid this endeavor.

    “The available crystal structures for some of these oncofusion proteins will aid this endeavor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Incomplete inhibition of a POI with SMIs may be tolerable, while complete depletion with a PROTAC might be detrimental if the POI is essential for normal cell function.

    “The incomplete inhibition of a POI with SMIs may be tolerable [203], while their complete depletion with a PROTAC might be detrimental if the POI is essential for normal cell function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Strelow JM. A perspective on the kinetics of covalent and irreversible inhibition. SLAS Discov. 2017;22:3–20. source

      Not checked in the free run.

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

    Premisenone given

    To date, two PROTACs have entered into clinical trials for the treatment of prostate and breast cancers.

    “To date, two PROTACs have entered into clinical trials for the treatment of prostate and breast cancers.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The high molecular weight and complex structure of PROTACs makes some PROTACs have low in vivo efficacy.

    “the high molecular weight and complex structure of PROTACs makes some of the PROTACs have low in vivo efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Breakthroughs in scRNA-seq have greatly enhanced our ability to determine cell-type specific transcriptomes and enable us to understand the profile of oncogenic targets and E3 ligases at the single-cell level.

    “Breakthroughs in scRNA-seq have greatly enhanced our ability to determine cell-type specific transcriptomes [12], and enable us to understand the profile of oncogenic targets and E3 ligases at the single-cell level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Han X, Zhou Z, Fei L, Sun H, Wang R, Chen Y, et al. Construction of a human cell landscape at single-cell level. Nature. 2020;581:303–9. source

      Not checked in the free run.

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

    Interpretationreasoning

    The development of tumor-specific/selective PROTACs based on cell-type and tumor-specific/selective E3 ligases may revolutionize the field of PROTACs as antitumor therapeutics.

    “The development of tumor-specific/selective PROTACs based on cell-type and tumor-specific/selective E3 ligases may revolutionize the field of PROTACs as antitumor therapeutics.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    ARV-471 is currently in a phase I clinical trial (NCT04072952).

    “ARV-471 is currently in a phase I clinical trial (NCT04072952).”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    ARV-471 is a PROTAC designed to specifically target ER.

    “ARV-471 is a PROTAC designed to specifically target ER.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    This can be accomplished by profiling E3 ligase expression at a cellular level.

    “This can be accomplished by profiling E3 ligase expression at a cellular level as discussed below.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Targeted protein degradation using PROTACs has emerged as a novel therapeutic modality in drug discovery.

    “Targeted protein degradation using PROTACs has emerged as a novel therapeutic modality in drug discovery.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    ARV-110 is an orally bioavailable AR PROTAC that entered into a clinical trial to treat patients with metastatic castrate-resistant prostate cancer (NCT03888612) in 2019.

    “ARV-110 is an orally bioavailable AR PROTAC that entered into a clinical trial to treat patients with metastatic castrate-resistant prostate cancer (NCT03888612) in 2019.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Based on scRNA-seq, we can choose more specific E3 ligases to target POIs to improve the efficiency of PROTACs and maximally reduce the toxicities to normal cells, which may be particularly applicable for hematologic malignancies.

    “Based on this, we can choose more specific E3 ligases to target POIs to improve the efficiency of PROTACs and maximally reduce the toxicities to normal cells, which may be particularly applicable for hematologic malignancies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Although numerous PROTACs have been developed to target oncoproteins associated with hematologic malignancies, none has entered into clinical trials for this indication thus far.

    “although numerous PROTACs have been developed to target oncoproteins associated with hematologic malignancies, none has entered into the clinical trials for this indication thus far.”
    Quote in the paperNot a substantial claim
96 of 96

  • The paper relies on this without support.

    The E3 ligases used in PROTACs are expressed in the relevant target cells or tissues.

    “These PROTACs are expected to avoid the on-target degradation of POIs in cells or tissues where the specific/selective E3 ligases are not expressed.”

  • The paper relies on this without support.

    Numerous POIs are ubiquitously expressed in both tumor and normal tissues and are indispensable for normal cell functions.

    “However, numerous POIs are ubiquitously expressed in both tumor and normal tissues and are indispensable for normal cell functions.”

  • The paper relies on this without support.

    The recent advancement in scRNA-Seq technology has allowed us to profile gene expression at a single-cell level and deconvolute cell-type heterogeneity in tissues.

    “The recent advancement in the single-cell RNA-Seq (scRNA-Seq) technology has allowed us to profile gene expression at a single-cell level and deconvolute the cell-type heterogeneity in tissues.”
3 of 3

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?

  • PROTAC adopts event-driven pharmacology binding at any point within the structure of potential targets, unlike occupancy-mode small molecule inhibitors.

    “Unlike the occupancy mode of small molecule inhibitors, which increase the risk of off-target effects, PROTAC adopts the pattern of “event-driven” pharmacology binding at any point within the structure of potential targets (23, 24).”

    From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [23]

    The Introduction and Fig. 1 caption in “Advantages of using PROTACs over other approaches to inhibit a POI” describe PROTACs’ catalytic degradation of targets, in contrast to inhibitors that typically bind an active site. Table 1 also says PROTACs can target proteins without an active binding site. These passages support the event-driven contrast, but not the unrestricted claim that PROTACs can bind at any point within a target’s structure. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • PROTAC molecules exhibit improved therapeutic efficacy and minimized drug resistance because of the potential for unique catalytic recycling.

    “Third, PROTAC molecules exhibit improved therapeutic efficacy and minimized drug resistance because of the potential for unique catalytic recycling (23, 24).”

    From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [23]

    The Introduction (page unavailable) says PROTACs act catalytically, can produce stronger and longer-lasting effects than small-molecule inhibitors, and can overcome certain forms of inhibitor resistance. It presents these as potential advantages, not established improvements in therapeutic efficacy or a general minimization of resistance caused by catalytic recycling. The Conclusions (page unavailable) also report that resistance to some PROTACs has occurred after chronic treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The catalytic nature of PROTAC can achieve and maintain enhanced target degradation at low doses.

    “Moreover, the catalytic nature of PROTAC can achieve and maintain enhanced target degradation at low doses (23, 25).”

    From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [23]

  • 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 [144]

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.

  • KRT8 is described as both low and highly expressed in hematopoietic cells

    Major

    The paper says KRT8 is expressed at low levels in hematopoietic cells, but later includes it among the top 10 ubiquitously expressed E3 ligases in those cells.

  • CDK6 compound name differs within Table 2

    Minor

    The CDK6 row identifies the compound as YX-2-017, but its in vivo efficacy and degradation entries identify the administered compound as YX-2-107. The CDK6 section also names YX-2-107.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–81. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., & Zhou, D.
Affiliations
  • University of Florida (US)
  • University of Florida Health (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Zhou, Daohong
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2020-07-27
Volume
13
Issue
1
Pages
103-103
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-020-00924-z
PMC
PMC7384229
OpenAlex
W3044807330
Semantic Scholar
6bf5b759a25e9ce07202fa806cd9b850830046de
Cited by
126
References
243
Citations by year
2026: 18 · 2025: 23 · 2024: 19 · 2023: 20 · 2022: 29 · 2021: 12 · 2020: 3 · 2014: 1
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R01CA211963, R01CA219836, R01CA242003, R21CA223371, R01CA241191)
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
PROTACs, hematologic malignancies, ubiquitin-proteasome system, protein degradation, E3 ubiquitin ligase, on-target toxicity, anticancer agents, single-cell RNA sequencing
MeSH terms
Animals, Clinical Trials as Topic, Humans, Leukemia, Ligands, Lymphoma, Multiple Myeloma, Neoplasm Proteins, Neoplasms, Organ Specificity, Protein Processing, Post-Translational, Recombinant Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Ubiquitination, 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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