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Cited by 169Protein Degradation and InhibitorsChronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and Treatment

Bruton tyrosine kinase degradation as a therapeutic strategy for cancer

Open access
Dobrovolsky, Dennis, Wang, Eric S., Morrow, Sara, Leahy, Catharine, Faust, Tyler, Nowak, Radosław P., Donovan, Katherine A., Yang, Guang +5 more·2019·Blood
DOI 10.1182/blood-2018-07-862953PMC PMC6396177
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Abstract

The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule–induced BTK degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in potent suppression of signaling and proliferation in cancer cells and that BTK degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading BTK, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, “triple degradation” may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.

AI snapshot

Written from the paper’s full text.

TL;DR

Small-molecule BTK degraders suppress B-cell malignancy signaling and proliferation, degrade C481S-BTK, and can overcome ibrutinib resistance. The optimized triple degrader DD-03-171 degrades BTK, IKZF1, and IKZF3, reduces tumor burden, and extends survival in MCL patient-derived xenograft models.

Key findings

  • BTK degradation durably reduced BTK levels and inhibited downstream Erk1/2 phosphorylation; degradation was proteasome- and CRBN-dependent and was prevented by bortezomib, MLN-4924, lenalidomide, or CGI1746.
  • DD-03-171 degraded WT- and C481S-BTK and had antiproliferative potency in TMD8 cells expressing C481S-BTK (ED50 = 128 nM) versus ibrutinib (ED50 = 578 nM); in TMD8 + WT BTK, ibrutinib ED50 <1 nM, DD-03-171 ED50 = 29.2 nM, DD-03-007 ED50 = 44.3 nM, CGI1746 ED50 = 245 nM.
  • In Mino MCL cells, DD-03-171 had ED50 = 12 nM, compared with DD-04-118 ED50 = 69 nM, lenalidomide ED50 = 243 nM, CGI1746 ED50 = 3.7 µM, and ibrutinib ED50 >10 µM.
  • In DFBL-96069 MCL PDX mice, DD-03-171 reduced peripheral blood tumor burden and significantly extended survival compared with vehicle, ibrutinib, and lenalidomide cohorts; proteomics identified >125,000 unique peptides corresponding to >9,000 proteins, with only 2 proteins significantly altered by DD-03-171 or DD-04-118, including BTK.

Methods

  • Biochemical TR-FRET CRBN-BTK dimerization assays, cellular CRBN engagement assays, KINOMEscan selectivity profiling, immunoblots, CellTiter-Glo proliferation assays, and CalcuSyn synergy assays.
  • Cell models included Ramos B cells, TMD8 and HBL1 ABC DLBCL cells overexpressing WT- or C481S-BTK, and MCL lines Mino, Granta-519, and Maver-1; in vivo work used patient-derived xenografts engrafted into NSG mice.
  • Multiplexed TMT mass spectrometry proteomics was performed in Mino cells after 4-hour treatment, with data processed in Proteome Discoverer 2.2 and analyzed using limma in R.

Limitations

  • Stated: PROTACs may have suboptimal physicochemical properties for in vivo use; BTK degrader tissue-specific degradation may vary due to CRBN levels; ibrutinib and IMiD off-target effects are not recapitulated; resistance may arise through reduced uptake, increased efflux, BTK mutations, PLCγ2 or alternative NF-κB activation, or altered E3 ligase/proteasome function; and BTK/IKZF1 loss may cause profound B-cell lymphopenia requiring IV immune globulin and increasing infection risk.
  • Stated: in vivo IKZF1/3 degradation was complex—BTK inhibition alone upregulated IKZF1/3, and DD-03-171 reduced but did not fully overcome this compensatory upregulation.
  • Evident from the text: DD-03-171 did not extend survival in DFBL-44685-engrafted mice, and none of the four compounds had significant antiproliferative effects in Granta-519 MCL cells.

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

Integrity signals

Registry

Crossref · 10.1182/blood-2018-07-862953

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Small-molecule-induced BTK degradation has antiproliferative effects superior to inhibition alone in cancer cells.

    “Small-moleculeinduced BTK degradation has antiproliferative effects superior to inhibition alone in cancer cells.”
    Quote in the paperSubstantial claim
  • Findingown data

    DD-04-118 had minimal effects on IKZF1/3 levels in Mino MCL cells.

    “In contrast, DD-04-118, which only differs from DD-03-171 by a single atom (Figure 1A), had minimal effects on IKZF1/3 levels (Figure 4A).”
    Quote in the paperSubstantial claim
  • Findingown data

    DD-03-171 binds exclusively to BTK at a screening concentration of 1 mM across a panel of 468 kinases.

    “We also tested binding of DD-03-171 against a panel of 468 kinases (KINOMEscan) and found that similar to CGI1746, DD-03-171 binds exclusively to BTK at a screening concentration of 1 mM (Figure 1C).”
    Quote in the paperSubstantial claim
  • Findingown data

    The same pattern of C481S-BTK effect on ibrutinib versus degraders was true in HBL1 ABC DLBCL cells.

    “this was similarly true in HBL1 ABC DLBCL cells (supplemental Figure 1B).”
    Quote in the paperSubstantial claim
  • Findingown data

    BTK degraders had comparable BTK kinase inhibitory activity to the parent inhibitor CGI1746.

    “Importantly, degraders had comparable activity to the parent inhibitor, validating our choice of linker attachment site.”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    The paper describes highly potent and selective BTK degraders with efficacy in cellular models of lymphoma and leukemia that can circumvent ibrutinib resistance.

    “Specifically, we describe highly potent and selective BTK degraders with efficacy in cellular models of lymphoma and leukemia that can circumvent ibrutinib resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C481S-BTK expression reduced the potency of ibrutinib approximately 1000-fold but had minimal effects on the potency of DD-03-007 or DD-03-171 in TMD8 ABC DLBCL cells.

    “While C481S-BTK expression reduced the potency of ibrutinib ;1000-fold, it had minimal effects on the potency of DD-03-007 or DD-03-171 (Figure 3B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chemical structure modifications enabled tuning of IKZF1/3 degradation activity, allowing synthesis of a degrader combining IKZF1/3 degradation with BTK degradation.

    “Moreover, we discovered that chemical structure modifications enabled us to tune IKZF1/3 degradation activity, allowing us to synthesize a degrader molecule that combined IKZF1/3 degradation with BTK degradation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The lead degrader DD-03-171 reduces tumor burden and extends survival in lymphoma patient-derived xenograft models.

    “The lead degrader DD-03-171 reduces tumor burden and extends survival in lymphoma patient-derived xenograft models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DD-03-007, DD-03-171, and DD-04-118 efficiently induced dimerization of BTK and CRBN, while lenalidomide and DD-03-033 did not.

    “Using a timeresolved FRET-based biochemical assay, we found that DD-03-007, DD-03-171, and DD-04-118 efficiently induced dimerization of BTK and CRBN, while neither lenalidomide nor the CRBNnonbinding compound DD-03-033 could do so (Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both DD-03-007 and DD-03-171 induced degradation of WT- and C481S-BTK, although DD-03-007 was slightly less potent.

    “Both degraders induced degradation of WT-and C481S-BTK, although DD-03-007 was slightly less potent (Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BTK degraders neither bind to nor degrade HCK.

    “our BTK degraders neither bind to nor degrade HCK (Figures 1C, 3A, and 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DD-03-171 potently degraded IKZF1/3 as well as BTK in Mino MCL cells.

    “we investigated whether DD-03-171 retained the activity of its imide moiety on IKZF1/3 and found that it potently degraded IKZF1/3 as well as BTK in Mino MCL cells (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both DD-03-007 and DD-03-171, but not DD-03-033, potently inhibited phosphorylation of Erk1/2, a downstream target of BTK, upon stimulation of the BCR.

    “Furthermore, both DD-03-007 and DD-03-171, but not DD-03-033, potently inhibited phosphorylation of Erk1/2, a downstream target of BTK, upon stimulation of the BCR (Figure 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both DD-03-007 and DD-03-171 significantly reduced cellular BTK levels at concentrations as low as 100 nM within 4 hours of treatment in Ramos B cells, while DD-03-033 did not.

    “Both DD-03-007 and DD-03-171 significantly reduced cellular BTK levels at concentrations as low as 100 nM within 4 hours of treatment, while DD-03-033, a negative control that does not bind CRBN, did not (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Excess lenalidomide or CGI1746 prevented BTK degradation by the degraders.

    “we performed competition experiments with either lenalidomide (for CRBN) or CGI1746 (for BTK) and found that excess quantities of either parent compounds could also prevent BTK degradation (Figure 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    DD-03-171 degrades IKZF1 and IKZF3 in vitro, with approximately 1.5-fold change for both proteins in Mino cells.

    “Moreover, in DD-03-171-treated cells, IKZF1 and IKZF3 were degraded (;1.5-fold change for both proteins, which did not meet our minimum twofold change threshold to be pictured on the scatterplot)”
    • Also stated in: § BTK degraders exhibit in vivo efficacy in MCL · boosted
      “While DD-03-171 efficiently degraded IKZF1/3 in vitro (Figure 4A)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    DD-03-171 has favorable pharmacokinetic and pharmacodynamic properties.

    “Here, we demonstrate that DD-03-171 has favorable pharmacokinetic and pharmacodynamic properties.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with either DD-03-171 or DD-04-118 resulted in significant alterations in protein abundance of only 2 proteins each, and BTK was one of those proteins in both cases.

    “Within the proteome, treatment with either DD-03-171 or DD-04-118 resulted in significant alterations in protein abundance of only 2 proteins each, and BTK was one of those proteins in both cases.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The BTK degraders exhibit antiproliferative effects.

    “antiproliferative effects”
    Quote in the paperSubstantial claim

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

    Findingown data

    Multiplexed mass spectrometry-based proteomic analysis of Mino cells after 4-hour treatment identified and quantified approximately 125,000 unique peptides corresponding to approximately 9,000 proteins.

    “Using abundance measurements from TMT isobaric labels, 41 whole-proteome analysis resulted in the identification and quantification of .125 000 unique peptides corresponding to .9000proteins.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Thalidomide interacts with CRBN to form a novel surface, resulting in interactions with neosubstrates IKZF1 and IKZF3 and their ubiquitination and proteasomal degradation.

    “thalidomide interacts with CRBN to form a novel surface, resulting in interactions with neosubstrates such as Ikaros (IKZF1) and Aiolos (IKZF3) and their ubiquitination and subsequent proteasomal degradation.20,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Krönke, 2014, Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells, Science source

      Not checked in the free run.

    • cites [21] Lu, 2014, The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The C481S mutation of BTK prevents ibrutinib from forming a covalent bond with BTK and significantly reduces its potency.

    “often due to the C481S mutation of BTK, which prevents ibrutinib from forming a covalent bond with BTK and significantly reduces its potency, resulting in median progression-free survival of only ;14 months.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Wang, 2013, Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma, N Engl J Med source

      Not checked in the free run.

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

    Study design and conductnone given

    Peptide spectral matches with poor quality MS3 spectra were excluded from quantitation, and resulting data were filtered to only include proteins with a minimum of 3 unique peptides.

    “Peptide spectral matches with poor quality MS3 spectra were excluded from quantitation (summed signal-to-noise across 10 channels ,200 and precursor isolation specificity ,0.5), and resulting data were filtered to only include proteins that had a minimum of 3 unique peptides identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The most common ibrutinib-resistant BTK mutant is C481S; other mutants include C481R, C481F, C481Y, T474I, and T474S.

    “While the most common ibrutinib-resistant BTK mutant is C481S, other mutants observed in patients include C481R, C481F, C481Y, T474I, and T474S.33”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Maddocks, 2015, Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia, JAMA Oncol source

      Not checked in the free run.

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

    Premisecitation

    Intrinsic ibrutinib resistance in MCL may be due in part to activation of nonclassical NF-kB signaling.

    “which may be due in part to activation of nonclassical NF-kB signaling.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Rahal, 2014, Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BTK degraders act in a proteasome- and CRBN-dependent manner.

    “Thus, these BTK degraders act in a proteasome-and CRBN-dependent manner.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The covalent BTK inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies.

    “The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    An ongoing clinical trial of ibrutinib, lenalidomide, and rituximab has reported promising initial responses.

    “Interestingly, an ongoing clinical trial of ibrutinib, lenalidomide, and the anti-CD20 antibody rituximab has reported promising initial responses.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Jerkeman, 2016, Ibrutinib-lenalidomide-rituximab in patients with relapsed/refractory mantle cell lymphoma: first results from the Nordic Lymphoma Group MCL6 (PHILEMON) phase II trial [abstract], Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many noncovalent BTK inhibitors have activity on WT and C481-mutant BTK with equal potency, and some consistently inhibit all mutants.

    “Many of these noncovalent inhibitors have activity on WT and C481-mutant BTK with equal potency, and some even consistently inhibit all mutants.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Johnson, 2016, Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations, ACS Chem Biol source

      Not checked in the free run.

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

    Premisecitation

    Ibrutinib and acalabrutinib have shown beneficial effects in patients with MCL and have received FDA approval for this indication.

    “As such, ibrutinib and the more selective BTK inhibitor acalabrutinib 39 have shown beneficial effects in patients with MCL and have received US Food and Drug Administration approval for this indication.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Wang, 2018, Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BTK is one of the most degraded kinases in a promiscuous kinase degrader proteomic analysis, indicating it is a tractable target for degradation.

    “Notably, BTK scored as one of the most degraded kinases, indicating that it is a tractable target.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Huang, 2018, A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader, Cell Chem Biol source

      Not checked in the free run.

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

    Study design and conductcitation

    PDX models were engrafted in NSG mice and handled according to an IACUC-approved protocol.

    “PDX models (supplemental Table 5, available on the Blood Web site) were engrafted in Nod.Cg-Prkdc scid IL2rg tm1Wjl /SzJ (NSG) mice purchased from The Jackson Laboratory and handled according to a Dana-Farber Cancer Institute's Institutional Animal Care and Use Committee-approved protocol (#13-034), as described previously.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Townsend, 2016, The public repository of xenografts enables discovery and randomized phase II-like trials in mice [published correction appears in Cancer Cell. 2016;30(1):183], Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DD-03-033 lacks a carbonyl on the glutarimide ring of the thalidomide moiety, a modification that significantly reduces its affinity for CRBN.

    “As a negative control, we synthesized DD-03-033 (Figure 1A), an analog of DD-03-007 that lacks a carbonyl on the glutarimide ring of the thalidomide moiety, a modification that significantly reduces its affinity for CRBN.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Huang, 2018, A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader, Cell Chem Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    IKZF1/3 degradation did occur in vivo but was not sufficient to overcome the compensatory upregulation of these 2 proteins in response to loss of BTK signaling.

    “suggesting that IKZF1/3 degradation did occur but was not sufficient to overcome the compensatory upregulation of these 2 proteins in response to loss of BTK signaling (Figure 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    No clinically approved HSP90 inhibitors exist, as most trials have been associated with limited efficacy and significant toxicity.

    “However, to date, there are no clinically approved HSP90 inhibitors, as most trials have been associated with limited efficacy and significant toxicity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Sidera, 2014, HSP90 inhibitors: current development and potential in cancer therapy, Recent Patents Anticancer Drug Discov source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    HSP90 inhibition induced almost complete loss of BTK and other client proteins.

    “Previously, we reported that HSP90 inhibition induced almost complete loss of BTK and other client proteins.10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Jacobson, 2016, HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are multiple mechanisms through which a lymphoma cell may be resistant to BTK degraders, including reduced uptake, increased efflux, mutations of BTK that block binding, activating mutations in PLCg2 or alternative NF-kB, or alterations that affect E3 ligase/proteasome function.

    “Third, there are multiple mechanisms through which a lymphoma cell may be resistant to BTK degraders, including reduced uptake, increased efflux, mutations of BTK that block binding, activating mutations in PLCg2 or alternative NF-kB, 7 or alterations that affect E3 ligase/proteasome function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Rahal, 2014, Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DD-04-118 differs from DD-03-171 by a single atom change of the thalidomide aryl amine nitrogen to an oxygen, predicted to compromise its ability to recruit IKZF1/3 to CRBN.

    “We also generated DD-04-118 (Figure 1A), an analog which differs from DD-03-171 by only a single atom change of the thalidomide aryl amine nitrogen to an oxygen, resulting in an aryl ether, a change that was predicted to compromise its ability to recruit IKZF1/3 to CRBN.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Nowak, 2018, Plasticity in binding confers selectivity in ligand-induced protein degradation, Nat Chem Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSP90 inhibition promotes degradation of different substrates in different tissues and rapidly induces stress responses that may mediate resistance.

    “presumably because HSP90 inhibition promotes the degradation of different substrates in different tissues and rapidly induces stress responses that may mediate resistance.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Sidera, 2014, HSP90 inhibitors: current development and potential in cancer therapy, Recent Patents Anticancer Drug Discov source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The combination of ibrutinib, lenalidomide, and rituximab has reported promising initial results.

    “The combination of ibrutinib, lenalidomide, and rituximab has reported promising initial results, 40”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Jerkeman, 2016, Ibrutinib-lenalidomide-rituximab in patients with relapsed/refractory mantle cell lymphoma: first results from the Nordic Lymphoma Group MCL6 (PHILEMON) phase II trial [abstract], Blood source

      Not checked in the free run.

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

    Interpretationnone given

    Targeting multiple proteins with a single molecule theoretically avoids potential adverse drug-drug interactions and offers more predictable pharmacokinetics than a drug combination, as well as simpler dosing for patients.

    “Theoretically, targeting multiple proteins with a single molecule avoids potential adverse drug-drug interactions and offers more predictable pharmacokinetics than a drug combination, as well as simpler dosing for patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    By converting a multitargeted kinase inhibitor into a degrader, the authors previously profiled the degradable kinome and identified BTK as a tractable target.

    “Previously, by converting a multitargeted kinase inhibitor into a degrader, we profiled the degradable kinome and identified BTK as a tractable target.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Huang, 2018, A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader, Cell Chem Biol source

      Not checked in the free run.

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

    Premisecitation

    In a recent report of a BTK degrader, target degradation varied significantly between the spleen and lung despite similar distribution, potentially due to differences in the tissue-specific levels of CRBN.

    “In a recent report of a BTK degrader, target degradation varied significantly between the spleen and lung despite similar distribution, potentially due to differences in the tissue-specific levels of CRBN.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Zorba, 2018, Delineating the role of cooperativity in the design of potent PROTACs for BTK, Proc Natl Acad Sci USA source

      Not checked in the free run.

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

    Premisenone given

    The DFBL-96069 model was derived from a patient who previously failed multiple rounds of therapy, including chemotherapy and ibrutinib.

    “This model was derived from a patient who previously failed multiple rounds of therapy, including chemotherapy and ibrutinib.”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    Efficacy of BTK degraders in cell lines and patient-derived xenograft models predicts therapeutic efficacy in patients with MCL and other B-cell malignancies.

    “Thus, combining BTK degradation with HCK inhibition (or other selective kinase inhibitors) may be a viable therapeutic strategy with reduced off-target effects compared with ibrutinib alone.”

  • The paper relies on this without support.

    The patient-derived xenograft models used are representative of human MCL and other B-cell lymphomas.

    “PDX models (supplemental Table 5, available on the Blood Web site) were engrafted in Nod.Cg-Prkdc scid IL2rg tm1Wjl /SzJ (NSG) mice purchased from The Jackson Laboratory and handled according to a Dana-Farber Cancer Institute's Institutional Animal Care and Use Committee-approved protocol (#13-034), as described previously.28”

  • The paper relies on this without support.

    BTK, IKZF1, and IKZF3 are validated targets in B-cell malignancies.

    “which combines degradation of BTK, IKZF1, and IKZF3, 3 validated targets in B-cell malignancies.”
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?

  • Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time.

    “Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time (Brand et al., 2019; Cromm et al., 2018; Dobrovolsky et al., 2019; Jiang et al., 2019; Li et al., 2019; Olson et al., 2018).”

    From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Dobrovolsky et al., 2019

  • Previous studies have shown that a nitrogen to oxygen modification on the thalidomide aryl attachment point can reduce or remove IMiD off-target effects in BTK and CDK4/6 targeted degraders.

    “Previous studies have shown that a nitrogen to oxygen modification on the thalidomide aryl attachment point can reduce or remove IMiD off-target effects in BTK and CDK4/6 targeted degraders (Dobrovolsky et al., 2019; Jiang et al., 2019).”

    From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Dobrovolsky et al., 2019

  • BTK is a well-established target in inflammation, as well as in oncology, with approved drugs in the clinic.

    “BTK is a well-established target in inflammation, as well as in oncology, with approved drugs in the clinic164,165”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [164]

  • Several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and in vivo potencies were reported.

    “Subsequently, several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and possessing in vivo potencies were reported by different groups [7, 44, 118–120].”

    From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [44]

  • Several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies.

    “several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies [3, 4, 44]”

    From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [44]

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References 47 · Cited by 169

Authors
Dobrovolsky, D., Wang, E. S., Morrow, S., Leahy, C., Faust, T., Nowak, R. P., Donovan, K. A., Yang, G., Li, Z., Fischer, E. S., Treon, S. P., Weinstock, D. M., & Gray, N. S.
Affiliations
  • Harvard University (US)
  • Department of Medical Oncology and
  • Dana-Farber Cancer Institute (US)
  • Broad Institute (US)
Corresponding author
  • Dobrovolsky, Dennis
  • Wang, Eric S.
  • Morrow, Sara
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2019-02-28
Volume
133
Issue
9
Pages
952-961
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2018-07-862953
PMC
PMC6396177
OpenAlex
W2905558559
Semantic Scholar
1171362cf88a60659a15944738e3f32acc6e8664
Cited by
169
References
47
Citations by year
2026: 10 · 2025: 20 · 2024: 23 · 2023: 21 · 2022: 33 · 2021: 26 · 2020: 21 · 2019: 14 · 2017: 1
FWCI
5.43
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Damon Runyon Cancer Research Foundation (DRR-50–18, DRG-2270-16)
  • Harvard University
  • National Institutes of Health
  • Natural Sciences and Engineering Research Council of Canada
  • National Cancer Institute (R01CA214608, R01CA218278)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
Bruton's tyrosine kinase, ibrutinib resistance, mantle cell lymphoma, B-cell lymphoma, small-molecule degraders, patient-derived xenografts, antiproliferative activity
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Animals, Antineoplastic Agents, Humans, Piperidines, Pyrazoles, Pyrimidines, Tumor Cells, Cultured, Signal Transduction, Mice, SCID, Mice, Inbred NOD, Lymphoma, Mantle-Cell, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Ikaros Transcription Factor, Small Molecule Libraries, 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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