CoChat
Sign Up
Cited by 1,561T-cell and B-cell ImmunologyLymphoma Diagnosis and TreatmentChronic Lymphocytic Leukemia Research

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Open access
Honigberg, Lee A., Smith, Ashley M., Sirisawad, Mint, Verner, Erik, Loury, David, Chang, Betty, Li, Shyr, Pan, Zhengying +3 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1004594107PMC PMC2919935
Open this paper in CoChat — free account

Abstract

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1004594107

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Mutations have not been observed in other kinases containing C481, including ITK and BLK, in patients with acquired resistance.

    “mutations have not been observed in these other targets, findings that suggest that BTK is its critical target.”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [7]

    The Discussion reports that BTK inhibition correlated with efficacy in a mouse arthritis model, consistent with BTK being a relevant target in vivo. It does not report acquired-resistance mutations in patients or establish that mutations were absent from ITK, BLK, or other targets. It also says a role for other cysteine-containing kinases cannot be ruled out. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • Ibrutinib inhibits other similar kinases that contain C481, including ITK and BLK.

    “Although ibrutinib inhibits other similar kinases that contain C481, including ITK and BLK,7,22”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [7]

    The Discussion (page unavailable) says PCI-32765 binds BTK at Cys-481 and that inhibition of other cysteine-containing kinases, including BLK, cannot be ruled out. It does not establish BLK inhibition or identify ITK as a kinase inhibited by PCI-32765, so the claim is stronger and more specific than this paper supports. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • At relapse, none of the six patients had mutations in other kinases containing a cysteine residue homologous to C481 in BTK that are irreversibly inhibited by ibrutinib.

    “At relapse, none of the patients had mutations in other kinases containing a cysteine residue homologous to C481 in BTK that are irreversibly inhibited by ibrutinib”

    From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [7]

    The Results and Discussion describe PCI-32765 binding to BTK at Cys-481 and note that a small subset of other kinases has a homologous cysteine. Neither section reports sequencing patients at relapse or whether any had mutations in those kinases; searches for relapse and patient mutations found no such result in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 27

  1. [1]Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and function: A genetic perspective. Immunol Rev. 2000;175:120–127. [PubMed] [Google Scholar]
  2. [2]Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol Res. 2001;23:147–156. doi: 10.1385/IR:23:2-3:147. [DOI] [PubMed] [Google Scholar] · DOI
  3. [3]Afar DE, et al. Regulation of Btk by Src family tyrosine kinases. Mol Cell Biol. 1996;16:3465–3471. doi: 10.1128/mcb.16.7.3465. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [4]Cheng G, Ye ZS. Baltimore D binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc Natl Acad Sci USA. 1994;91:8152–8155. doi: 10.1073/pnas.91.17.8152. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. [5]Humphries LA, et al. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker. J Biol Chem. 2004;279:37651–37661. doi: 10.1074/jbc.M311985200. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Conley ME, et al. Primary B cell immunodeficiencies: Comparisons and contrasts. Annu Rev Immunol. 2009;27:199–227. doi: 10.1146/annurev.immunol.021908.132649. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Tsukada S, Rawlings DJ, Witte ON. Role of Bruton's tyrosine kinase in immunodeficiency. Curr Opin Immunol. 1994;6:623–630. doi: 10.1016/0952-7915(94)90151-1. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Rawlings DJ, et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science. 1993;261:358–361. doi: 10.1126/science.8332901. [DOI] [PubMed] [Google Scholar] · DOI
  9. [9]Satterthwaite AB, Cheroutre H, Khan WN, Sideras P, Witte ON. Btk dosage determines sensitivity to B cell antigen receptor cross-linking. Proc Natl Acad Sci USA. 1997;94:13152–13157. doi: 10.1073/pnas.94.24.13152. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. [10]Texido G, et al. The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Mol Cell Biol. 2000;20:1227–1233. doi: 10.1128/mcb.20.4.1227-1233.2000. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. [11]Lowell CA. Src-family kinases: Rheostats of immune cell signaling. Mol Immunol. 2004;41:631–643. doi: 10.1016/j.molimm.2004.04.010. [DOI] [PubMed] [Google Scholar] · DOI
  12. [13]Favas C, Isenberg DA. B-cell-depletion therapy in SLE—what are the current prospects for its acceptance? Nat Rev Rheumatol. 2009;5:711–716. doi: 10.1038/nrrheum.2009.218. [DOI] [PubMed] [Google Scholar] · DOI
  13. [14]Hauser SL, et al. HERMES Trial Group B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–688. doi: 10.1056/NEJMoa0706383. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. [15]Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5:251–262. doi: 10.1038/nrc1589. [DOI] [PubMed] [Google Scholar] · DOI
  15. [16]Davis RE, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92. doi: 10.1038/nature08638. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [17]Pan Z, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007;2:58–61. doi: 10.1002/cmdc.200600221. [DOI] [PubMed] [Google Scholar] · DOI
  17. [18]Marcotte DJ, et al. Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases. Protein Sci. 2010;19:429–439. doi: 10.1002/pro.321. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. [19]Jansson L, Holmdahl R. Genes on the X chromosome affect development of collagen-induced arthritis in mice. Clin Exp Immunol. 1993;94:459–465. doi: 10.1111/j.1365-2249.1993.tb08218.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. [20]Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med. 1994;180:1295–1306. doi: 10.1084/jem.180.4.1295. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. [21]Breen M, Modiano JF. Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans—man and his best friend share more than companionship. Chromosome Res. 2008;16:145–154. doi: 10.1007/s10577-007-1212-4. [DOI] [PubMed] [Google Scholar] · DOI
  21. [22]Fry DW, et al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci USA. 1998;95:12022–12027. doi: 10.1073/pnas.95.20.12022. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [23]Cohen MS, Zhang C, Shokat KM, Taunton J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005;308:1318–1321. doi: 10.1126/science1108367. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. [24]Yanaba K, et al. B cell depletion delays collagen-induced arthritis in mice: Arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol. 2007;179:1369–1380. doi: 10.4049/jimmunol.179.2.1369. [DOI] [PubMed] [Google Scholar] · DOI
  24. [25]Chen L, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 2008;111:2230–2237. doi: 10.1182/blood-2007-07-100115. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [26]Chan O, Madaio MP, Shlomchik MJ. The roles of B cells in MRL/lpr murine lupus. Ann N Y Acad Sci. 1997;815:75–87. doi: 10.1111/j.1749-6632.1997.tb52046.x. [DOI] [PubMed] [Google Scholar] · DOI
  26. [27]Vail DM. Veterinary Co-operative Oncology Group - Common Terminology Criteria for Adverse Events following chemotherapy or biological antineoplastic therapy in dogs and cats. Vet Comp Oncol. 2004;2:194–213. doi: 10.1111/j.1476-5810.2004.0053b.x. [DOI] [PubMed] [Google Scholar] · DOI
  27. [28]Vail DM, Michels GM, Khanna C, Selting KA, London CA. Veterinary Cooperative Oncology Group Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol. 2010;8:28–37. doi: 10.1111/j.1476-5829.2009.00200.x. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., & Buggy, J. J.
Affiliations
  • Pharmacyclics (United States) (US)
  • Exelixis (United States) (US)
  • Peking University (CN)
  • Colorado State University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-07-06
Volume
107
Issue
29
Pages
13075-13080
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1004594107
PMC
PMC2919935
OpenAlex
W2163690533
Cited by
1,561
References
1
Citations by year
2026: 52 · 2025: 83 · 2024: 79 · 2023: 98 · 2022: 94 · 2021: 137 · 2020: 109 · 2019: 116 · 2018: 118 · 2017: 125 · 2016: 116 · 2015: 142 · 2014: 103 · 2013: 87 · 2012: 70
FWCI
26.54
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
Bruton's tyrosine kinase, B cell receptor signaling, B cell activation, autoimmune disease, collagen-induced arthritis, autoantibodies, kidney disease, B-cell non-Hodgkin lymphoma, irreversible kinase inhibitors, dogs
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Administration, Oral, Animals, Arthritis, Experimental, Autoantibodies, Autoimmune Diseases, B-Lymphocytes, Benzofurans, Disease Models, Animal, Dogs, Humans, Lymphocyte Activation, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Signal Transduction, Lymphoma, B-Cell, Treatment Outcome, Protein Kinase Inhibitors, Mice

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.

Statistics and arithmetic are recomputed, not judged.

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

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

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