ArticleMolecular cancer therapeutics2024
Bruton's Tyrosine Kinase Inhibitors with Distinct Binding Modes Reveal Differential Functional Impact on B-Cell Receptor Signaling.
Article in Molecular cancer therapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The trial behind it
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
10 citing papers in PubMed, 18 citations in OpenAlex.
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Design, synthesis, and anticancer activity of phenoxyacetohydrazide derivatives in burkitt lymphoma.Scientific reports · 2026Article
- More than an attachment module: covalent inhibitor warheads influence BTK dynamics and function.bioRxiv : the preprint server for biology · 2026Article
- Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease.Molecules (Basel, Switzerland) · 2026Review
- Exploring pocket-aware inhibitors of BTK kinase by generative deep learning, molecular docking, and molecular dynamics simulations.RSC advances · 2025Article
- BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies.Archives of pharmacal research · 2025Review
- Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.Science signaling · 2025Article
- Article
- Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.Acta pharmacologica Sinica · 2024Article
- Review
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Small molecule inhibitors of Bruton's tyrosine kinase (BTK) have been approved for the treatment of multiple B-cell malignancies and are being evaluated for autoimmune and inflammatory diseases. Various BTK inhibitors (BTKi) have distinct potencies, selectivity profiles, and binding modes within the ATP-binding site. On the basis of the latter feature, BTKis can be classified into those that occupy the back-pocket, H3 pocket, and the hinge region only. Hypothesizing that differing binding modes may have differential impact on the B-cell receptor (BCR) signaling pathway, we evaluated the activities of multiple BTKis in B-cell lymphoma models in vitro and in vivo. We demonstrated that, although all three types of BTKis potently inhibited BTK-Y223 autophosphorylation and phospholipase C gamma 2 (PLCγ2)-Y1217 transphosphorylation, hinge-only binders were defective in inhibiting BTK-mediated calcium mobilization upon BCR activation. In addition, PLCγ2 activation was effectively blocked by back-pocket and H3 pocket binders but not by hinge-only binders. Further investigation using TMD8 cells deficient in Rac family small GTPase 2 (RAC2) revealed that RAC2 functioned as a bypass mechanism, allowing for residual BCR signaling and PLCγ2 activation when BTK kinase activity was fully inhibited by the hinge-only binders. These data reveal a kinase activity-independent function of BTK, involving RAC2 in transducing BCR signaling events, and provide mechanistic rationale for the selection of clinical candidates for B-cell lymphoma indications.
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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 Socratic graph.