ArticleBlood advances2020
Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.Frontiers in immunology · 2021Pooled it
- Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges.Annals of hematology · 2025Review
- The contribution of BTK signaling in myeloid cells to neuroinflammation.Frontiers in immunology · 2025Article
- In BTK, phosphorylated Y223 in the SH3 domain mirrors catalytic activity, but does not influence biological function.Blood advances · 2024Article
- Impact of ibrutinib on inflammation in a mouse model of Graves' orbitopathy.Frontiers in endocrinology · 2024Article
- Kinase Inhibition in Multiple Myeloma: Current Scenario and Clinical Perspectives.Pharmaceutics · 2022Review
- Review
- Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs).Angewandte Chemie (International ed. in English) · 2022Article
- Review
- Article
- Ibrutinib Has Time-dependent On- and Off-target Effects on Plasma Biomarkers and Immune Cells in Chronic Lymphocytic Leukemia.HemaSphere · 2021Article
- BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects.Frontiers in immunology · 2021Review
- Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway.Frontiers in immunology · 2021Review
- Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects.Frontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pharmacological inhibitors of Bruton tyrosine kinase (BTK) have revolutionized treatment of B-lymphocyte malignancies and show great promise for dampening autoimmunity. The predominant BTK inhibitors tether irreversibly by covalently binding to cysteine 481 in the BTK catalytic domain. Substitution of cysteine 481 for serine (C481S) is the most common mechanism for acquired drug resistance. We generated a novel C481S knock-in mouse model and, using a battery of tests, no overt B-lymphocyte phenotype was found. B lymphocytes from C481S animals were resistant to irreversible, but sensitive to reversible, BTK inhibitors. In contrast, irreversible inhibitors equally impaired T-lymphocyte activation in mice, mimicking the effect of treatment in patients. This demonstrates that T-lymphocyte blockage is independent of BTK. We suggest that the C481S knock-in mouse can serve as a useful tool for the study of BTK-independent effects of irreversible inhibitors, allowing for the identification of novel therapeutic targets and pinpointing potential side effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.