The DOI matches its Crossref record; 48 of the 49 references it cites were found in a registry or an index.
Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes
Open accessAbstract
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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In the citing paper
“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 [22]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [22]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [22]
Experimental — accuracy not yet measured
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“Irreversible ITK binding, ITK signal inhibition, and Th1-skewed cytokine patterns were also identified in CLL patients treated with ibrutinib in 2 clinical trials.(37,38) These findings were validated using a well-established mouse model of cutaneous leishmaniasis, and further clinical relevance was demonstrated using…”
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The B-cell receptor signaling pathway as a therapeutic target in CLL
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Self-citationRequirement for Tec Kinases Rlk and Itk in T Cell Receptor Signaling and Immunity
Schaeffer, E. M., Debnath, J., Yap, G. S., McVicar, D. W., Liao, X. C., Littman, D. R., Sher, A., VARMUS, H. E., Lenardo, M. J., & Schwartzberg, P. L. (1999) · Science · doi:10.1126/science.284.5414.638 · Cited by 398
TEC FAMILY KINASES IN T LYMPHOCYTE DEVELOPMENT AND FUNCTION
Berg, L. J., Finkelstein, L. D., Lucas, J. A., & Schwartzberg, P. L. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104743 · Cited by 341
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Zhang, J. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1903660
Genetic orchestration of the primary central nervous system lymphoma microenvironment
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Metadata
- Authors
- Dubovsky, J. A., Beckwith, K. A., Natarajan, G., Woyach, J. A., Jaglowski, S., Zhong, Y., Hessler, J. D., Liu, T.-M., Chang, B. Y., Larkin, K. M., Stefanovski, M. R., Chappell, D. L., Frissora, F. W., Smith, L. L., Smucker, K. A., Flynn, J. M., Jones, J. A., Andritsos, L. A., Maddocks, K., Lehman, A. M., Furman, R., Sharman, J., Mishra, A., Caligiuri, M. A., Satoskar, A. R., Buggy, J. J., Muthusamy, N., Johnson, A. J., & Byrd, J. C.
- Affiliations
- Department of Internal Medicine, Division of Hematology,
- The Ohio State University (US)
- Pharmacyclics (United States) (US)
- Weill Cornell Medicine (US)
- Willamette Valley Cancer Institute and Research Center (US)
- Department of Pathology, and
- ORCID
- Beckwith, Kyle A.
- Natarajan, Gayathri
- Woyach, Jennifer A.
- Jaglowski, Samantha
- Chang, Betty Y.
- Chappell, Danielle L.
- Smith, Lisa L.
- Flynn, Joseph M.
- Jones, Jeffrey A.
- Andritsos, Leslie A.
- Maddocks, Kami
- Furman, Richard
- Sharman, Jeff
- Mishra, Anjali
- Caligiuri, Michael A.
- Satoskar, Abhay R.
- Muthusamy, Natarajan
- Johnson, Amy J.
- Byrd, John C.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-10-10
- Volume
- 122
- Issue
- 15
- Pages
- 2539-2549
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3795457
- OpenAlex
- W2089103836
- Cited by
- 810
- References
- 49
- Citations by year
- 2026: 30 · 2025: 43 · 2024: 55 · 2023: 51 · 2022: 70 · 2021: 98 · 2020: 68 · 2019: 71 · 2018: 71 · 2017: 70 · 2016: 65 · 2015: 67 · 2014: 43 · 2013: 5
- FWCI
- 29.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16)
- National Cancer Institute (P01CA095426, P50CA140158, T32CA009338, 5 T32 CA009338-33-03, P30CA016058, K12CA133250, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- ibrutinib, irreversible kinase inhibitors, Bruton's tyrosine kinase, T cell signaling, Th1 response, Th2 immune response, chronic lymphocytic leukemia, Leishmania major, Listeria monocytogenes, immunomodulation
- MeSH terms
- Adenine, Animals, Disease Models, Animal, Enzyme Inhibitors, Humans, Leukemia, Listeriosis, Lymphocyte Activation, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leishmaniasis, Cutaneous, CD8-Positive T-Lymphocytes, Th1 Cells, Th2 Cells, Jurkat Cells, Mice, Primary Cell Culture
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