ArticleJCI insight2019
Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activity.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents.Frontiers in oncology · 2020Pooled it
- 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
- Lysine Targeting Group-Transfer Chimeras for Proximity Induction.Angewandte Chemie (International ed. in English) · 2026Article
- Article
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.Science signaling · 2025Article
- Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib.Blood advances · 2024Article
- The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas.International journal of molecular sciences · 2024Review
- Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma.Blood advances · 2023Article
- BTK mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib.Blood advances · 2023Article
- Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ.Communications biology · 2023Article
- Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.Blood advances · 2022Article
- A mechanism for localized dynamics-driven activation in Bruton's tyrosine kinase.Royal Society open science · 2021Article
- Article
- Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors.Frontiers in immunology · 2021Review
- Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects.Blood advances · 2020Article
- Cell line-based assessment of BTK inhibitors.British journal of pharmacology · 2020Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Inhibition of Bruton tyrosine kinase (BTK) is a breakthrough therapy for certain B cell lymphomas and B cell chronic lymphatic leukemia. Covalent BTK inhibitors (e.g., ibrutinib) bind to cysteine C481, and mutations of this residue confer clinical resistance. This has led to the development of noncovalent BTK inhibitors that do not require binding to cysteine C481. These new compounds are now entering clinical trials. In a systematic BTK mutagenesis screen, we identify residues that are critical for the activity of noncovalent inhibitors. These include a gatekeeper residue (T474) and mutations in the kinase domain. Strikingly, co-occurrence of gatekeeper and kinase domain lesions (L512M, E513G, F517L, L547P) in cis results in a 10- to 15-fold gain of BTK kinase activity and de novo transforming potential in vitro and in vivo. Computational BTK structure analyses reveal how these lesions disrupt an intramolecular mechanism that attenuates BTK activation. Our findings anticipate clinical resistance mechanisms to a new class of noncovalent BTK inhibitors and reveal intramolecular mechanisms that constrain BTK's transforming potential.
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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.