ArticleLeukemia2021
BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib.
Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
51 citing papers in PubMed, 72 citations in OpenAlex.
- Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations.Blood cancer journal · 2026Trial
- Trial
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles.bioRxiv : the preprint server for biology · 2026Article
- Review
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- Zanubrutinib in B-cell lymphomas: from clinical pharmacology to therapeutic application.European journal of clinical pharmacology · 2026Review
- BTK Inhibition in Hematology: From CLL/SLL to Emerging Applications Across B-Cell and Immune Disorders.Biomolecules · 2026Review
- An overview of advanced nanocarrier systems for Ibrutinib delivery: overcoming pharmacokinetic barriers and enabling targeted cancer therapy.International journal of pharmaceutics: X · 2025Review
- Microsecond simulations to investigate the structural mechanism of super-resistant double mutations in BTK to the covalent inhibitor ibrutinib in multiple leukemia.Scientific reports · 2025Article
- Article
- A paradigm shift: analytical ultracentrifugation as a multi-attribute platform method in targeted protein degradation.European biophysics journal : EBJ · 2025Article
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies.Archives of pharmacal research · 2025Review
- Bruton's Tyrosine Kinase Inhibitors: A Versatile Therapeutic Approach for Cancer, Autoimmune Disorders, GVHD and COVID-19.Mini reviews in medicinal chemistry · 2025Review
- Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia.Nature reviews. Clinical oncology · 2024Review
- Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib.Blood advances · 2024Article
- Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities.HemaSphere · 2024Review
- Development of combination therapies with BTK inhibitors and dasatinib to treat CNS-infiltrating E2A-PBX1+/preBCR+ ALL.Blood advances · 2024Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the "gatekeeper" residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
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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.