Affinage

BTK

Tyrosine-protein kinase BTK · UniProt Q06187

Length
659 aa
Mass
76.3 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BTK is a cytoplasmic Tec-family tyrosine kinase that transduces B-cell receptor (BCR) signaling and is essential for normal B-cell development, its loss producing the murine Xid phenotype with B1-cell deficiency and impaired antibody responses (PMID:7552994). The protein is held in an autoinhibited compact conformation stabilized by its PH-TH module together with the SH2 and SH3 domains, and is activated either at PIP3-containing membranes or, uniquely among Tec kinases, by inositol hexakisphosphate (IP6) that drives transient PH-TH dimerization and kinase transphosphorylation (PMID:25699547). Within the BCR pathway, BLNK scaffolds Syk to phosphorylate BTK on Y551 via the BTK SH2 domain, and BCR-induced BTK activation is lost in BLNK- or Syk-deficient B cells (PMID:11226282); downstream BTK occupies a position between PI3K and PLCγ2, where it controls integrin α4β1-mediated adhesion through PLCγ2/IP3R-driven Ca2+ release and cytoskeletal reorganization (PMID:14610042). Through canonical NF-κB activation BTK drives transcription of anti-apoptotic and proliferative genes including BCL2 in mantle cell lymphoma (PMID:27157620), and it acts as a direct kinase of the NLRP3 inflammasome, phosphorylating conserved tyrosines to promote NLRP3 relocalization, oligomerization, ASC polymerization and IL-1β release (PMID:34554188). BTK function extends to innate immunity, where it is required for TLR3-triggered NK-cell activation via NF-κB (PMID:22589540) and for fungus-induced neutrophil oxidative burst through p40phox and RAC2 activation (PMID:38696257). Clinically important resistance to covalent BTK inhibitors arises through kinase-dead C481 scaffold mutants that recruit and activate HCK to sustain PLCγ2 signaling independently of BTK catalytic activity (PMID:35639855), a liability addressed by noncovalent inhibitors that bind outside C481 and lock BTK in a closed conformation (PMID:36796019) and by degraders that eliminate all mutant proteoforms (PMID:38301010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Established that BTK is genetically required for B-cell development, defining the loss-of-function phenotype and linking the gene to humoral immunodeficiency.

    Evidence Targeted knockout of PH or kinase domain in mice with B-cell activation and immunization assays

    PMID:7552994

    Open questions at the time
    • Does not resolve the biochemical signaling step BTK occupies
    • Phenotype defined in mouse; human XLA correspondence inferred
  2. 1999 Medium

    Identified a constitutive PH-TH-mediated association between BTK and PKCmu, an early clue to BTK's protein interaction surface.

    Evidence Co-IP and GST pulldown with PKCmu domain constructs in 293T cells

    PMID:10561498

    Open questions at the time
    • Functional consequence of the interaction undefined
    • Overexpression in transfected cells, single lab
  3. 2001 High

    Placed BTK activation within the BCR proximal cascade by showing BLNK scaffolds Syk to phosphorylate BTK on Y551, resolving how upstream kinases engage BTK.

    Evidence Reconstitution co-expression, Y551 phosphorylation assay, SH2 interaction mapping, BLNK/Syk-deficient B cells

    PMID:11226282

    Open questions at the time
    • Does not address membrane recruitment via PH domain
    • Y551 dynamics under physiological BCR engagement not quantified
  4. 2003 High

    Positioned BTK between PI3K and PLCγ2 in integrin signaling, extending its role beyond Ca2+ flux to adhesion and cytoskeletal control.

    Evidence Genetic and pharmacological dissection of VLA-4-mediated B-cell adhesion to VCAM-1/fibronectin

    PMID:14610042

    Open questions at the time
    • Direct BTK substrates in the adhesion pathway not pinpointed
    • Pre-B versus mature B-cell contributions only partially separated
  5. 2003 Low

    Proposed a positive feedback loop in which BTK activates PIP5K to generate PI(4,5)P2 amplifying its own signal.

    Evidence Commentary citing primary BTK-PIP5K activation data

    PMID:14614849

    Open questions at the time
    • Claim drawn from a commentary, not direct experimental detail in this entry
    • Feedback stoichiometry and physiological relevance unquantified
  6. 2002 Medium

    Linked BTK to Akt/ERK/JNK signaling and oxidative stress responses, broadening BTK's downstream signaling reach.

    Evidence Reciprocal co-IP of endogenous BTK and Akt, co-localization, kinase assays with PI3K inhibitors in B-cell lines

    PMID:12054657

    Open questions at the time
    • Direct versus indirect BTK-Akt interaction not distinguished
    • Single lab without genetic confirmation of the kinase relationships
  7. 1998 Medium

    Implicated BTK as a bidirectional regulator of apoptosis, promoting radiation-induced death yet inhibiting Fas-DISC assembly.

    Evidence Co-IP of BTK with Fas, radiation and Fas-ligation apoptosis assays, STAT-3 activity measurement

    PMID:9751072

    Open questions at the time
    • Molecular basis of dual role not reconciled
    • Single lab, two orthogonal methods
  8. 2012 High

    Extended BTK function to innate immunity by showing it is required for TLR3-triggered NK-cell activation through NF-κB.

    Evidence Btk-/- mouse NK-cell assays, NF-κB analysis, adoptive transfer, XLA patient NK cells

    PMID:22589540

    Open questions at the time
    • Direct BTK substrates in TLR3-NK signaling not identified
    • Mechanism of TLR3-to-BTK coupling unresolved
  9. 2015 High

    Defined the structural basis of BTK autoinhibition and revealed a BTK-unique IP6-induced PH-TH dimerization activation mode, resolving how BTK is switched on.

    Evidence X-ray crystallography, lipid-binding and kinase assays, mutagenesis, sequence comparisons

    PMID:25699547

    Open questions at the time
    • Cellular concentration thresholds for IP6 activation not established
    • Integration of IP6 and PIP3 activation in vivo unclear
  10. 2016 Medium

    Connected BTK to a pro-survival transcriptional program, showing it upregulates BCL2 and other anti-apoptotic/proliferative genes via NF-κB in lymphoma.

    Evidence shRNA knockdown with RNA-seq, NF-κB reporter assays, tissue microarray in mantle cell lymphoma

    PMID:27157620

    Open questions at the time
    • Direct versus indirect transcriptional effects not separated
    • Single lab
  11. 2016 Medium

    Identified BTK as a p53 modulator forming a DNA-damage-induced positive feedback loop that enhances p53-dependent senescence and apoptosis.

    Evidence BTK induction by DNA damage, inhibitor treatment, p53 phosphorylation and functional senescence/apoptosis assays

    PMID:27630139

    Open questions at the time
    • Direct kinase relationship to p53 not biochemically defined
    • Single lab
  12. 2021 High

    Established BTK as a direct NLRP3 kinase, phosphorylating conserved tyrosines to drive inflammasome assembly and IL-1β release.

    Evidence Co-IP, in vitro and in vivo kinase assays, NLRP3 localization/oligomerization, ASC polymerization, IL-1β assays

    PMID:34554188

    Open questions at the time
    • Stoichiometry of NLRP3 phosphosites in vivo not fully mapped
    • Relative contribution versus other NLRP3 regulators unclear
  13. 2021 High

    Demonstrated a receptor-selective platelet role for BTK, essential in CLEC-2 but only modulatory in GPVI signaling, informing inhibitor bleeding risk.

    Evidence Platelet activation/phosphorylation assays, inhibitor dose-response, XLA patient platelets, in vivo thrombosis models

    PMID:31949019

    Open questions at the time
    • Molecular basis of CLEC-2 versus GPVI selectivity not fully defined
  14. 2024 High

    Showed BTK drives fungus-induced neutrophil oxidative burst via p40phox and RAC2, extending BTK's innate role to antifungal defense.

    Evidence Neutrophil-specific conditional Btk knockout mice, XLA neutrophils, inhibitor studies, p40phox/RAC2 activation assays, aspergillosis models

    PMID:38696257

    Open questions at the time
    • Direct BTK substrate in NADPH oxidase assembly not identified
    • Pathway from TLR2/Dectin-1/FcγR to BTK not fully mapped
  15. 2024 Medium

    Revealed a metabolic role for BTK in macrophage fatty acid oxidation negatively regulated by a TREM2-SHP1 axis during sepsis.

    Evidence Co-IP of TREM2 with SHP1, Trem2 knockout mice, FAO and triglyceride assays, BTK activity assays, survival studies

    PMID:39405126

    Open questions at the time
    • Direct BTK substrates in FAO pathway undefined
    • Single lab
  16. 2022 High

    Uncovered a kinase-independent BTK scaffold mechanism of drug resistance, with kinase-dead C481F/Y mutants recruiting and activating HCK to sustain PLCγ2 signaling.

    Evidence Kinase assays, structural modeling, co-IP of BTK C481F/Y with HCK, Y551/PLCγ2/NF-κB phosphorylation, clonogenic assays

    PMID:35639855

    Open questions at the time
    • In vivo prevalence of the scaffold mechanism not quantified
  17. 2021 Medium

    Identified an alternative resistance route in which RAC2 epigenetically substitutes for BTK in activating PLCγ2/NF-κB.

    Evidence Ibrutinib-resistance modeling in ABC-DLBCL, genetic screens, RAC2/PLCγ2 interaction studies, patient CLL analysis

    PMID:34778802

    Open questions at the time
    • Mechanism of TCF4-driven RAC2 induction incompletely defined
    • Single lab
  18. 2020 High

    Provided structural insight into BTK-targeting degraders by characterizing ternary complexes with cIAP1, showing complex stability does not predict degradation efficiency.

    Evidence X-ray crystallography of BTK-cIAP1-degrader ternary complexes with degradation assays

    PMID:33199914

    Open questions at the time
    • Determinants of productive degradation beyond stability not fully resolved
  19. 2023 High

    Validated a noncovalent inhibitor strategy: pirtobrutinib binds outside C481, inhibits C481 mutants, and locks BTK in a closed conformation preventing Y551 phosphorylation.

    Evidence Structural binding studies, enzymatic and cellular assays, differential scanning fluorimetry, Y551 assays, xenografts

    PMID:36796019

    Open questions at the time
    • Does not address kinase-independent scaffold resistance
  20. 2024 High

    Demonstrated that targeted degradation overcomes both catalytic and scaffold resistance by eliminating all mutant BTK proteoforms, with clinical proof of concept.

    Evidence Mutant enzymatic characterization, interaction studies, proteasomal degradation assays, BCR blockade, CLL patient BTK degradation by NX-2127

    PMID:38301010

    Open questions at the time
    • Durability of clinical response and emergence of degrader resistance not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BTK's diverse roles—BCR signaling, inflammasome activation, innate oxidative burst, and macrophage metabolism—are coordinated and which direct substrates operate in each context remains incompletely defined.
  • Comprehensive direct substrate map across cell types lacking
  • Integration of distinct activation inputs (PIP3, IP6, scaffold) in vivo unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 2 GO:0140110 transcription regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
AKTBLNKFASHCKNLRP3PLCG2PRKD1SYK
Complex memberships
NLRP3 inflammasome

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Btk is required for normal B cell development in mice; targeted mutations eliminating the PH or kinase domain block Btk protein expression and result in reduced mature conventional B cells, severe B1 cell deficiency, serum IgM and IgG3 deficiency, and defective responses to B cell activators and thymus-independent type II antigens, proving that lack of Btk function produces the Xid phenotype. Gene targeting in embryonic stem cells (knockout of PH or kinase domain), RAG2-deficient blastocyst complementation, germline transmission, in vitro B cell activation assays, in vivo immunization Immunity High 7552994
2001 BLNK mediates Syk-dependent BTK activation in BCR signaling: in a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on tyrosine 551, enhancing Btk activity. This interaction requires the Btk SH2 domain binding to BLNK, and BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient or Syk-deficient B cells. Reconstitution cell system (co-expression), site-specific phosphorylation assay (Y551), SH2 domain interaction studies, BLNK-deficient and Syk-deficient B cell analysis Proceedings of the National Academy of Sciences of the United States of America High 11226282
2003 BCR-controlled integrin alpha4beta1 (VLA-4)-mediated adhesion of B cells to VCAM-1 and fibronectin requires the consecutive activation of Lyn, Syk, PI3K, Btk, PLCgamma2, IP3R-mediated Ca2+ release, and PKC. Btk is positioned between PI3K and PLCgamma2 in this pathway, and Btk is also involved in control of integrin-mediated adhesion of pre-B cells. Cytoskeletal reorganization and integrin clustering are downstream consequences. Biochemical, pharmacological, and genetic dissection; knockout B cells; pharmacological inhibitors; adhesion assays to VCAM-1 and fibronectin The Journal of experimental medicine High 14610042
2015 BTK adopts an autoinhibited compact conformation similar to inactive c-Src and c-Abl, stabilized by its PH-TH module together with SH2 and SH3 domains. BTK is activated by membranes containing PIP3. Additionally, inositol hexakisphosphate (IP6), a soluble signaling molecule, activates BTK by inducing transient PH-TH dimerization that promotes transphosphorylation of the kinase domains; this IP6-mediated activation is unique to BTK among Tec-family kinases. X-ray crystallography, biochemical autoinhibition assays, lipid-binding assays, in vitro kinase activity assays, mutational analysis, sequence comparisons eLife High 25699547
1999 Btk constitutively associates with protein kinase C mu (PKCmu) via its PH-TH domain; both the kinase domain and the regulatory C1 region of PKCmu independently bind the Btk PH-TH domain. This interaction is not affected by BCR crosslinking, phorbol ester, or H2O2 stimulation. Co-immunoprecipitation, GST pulldown, transient overexpression of PKCmu deletion mutants and domain constructs in 293T cells FEBS letters Medium 10561498
1998 BTK functions as a dual-function regulator of apoptosis: it promotes radiation-induced apoptosis (at least partly by down-regulating anti-apoptotic STAT-3 activity in response to reactive oxygen species) but inhibits Fas-activated apoptosis by associating with the death receptor Fas and impairing its interaction with FADD, thereby preventing assembly of the pro-apoptotic DISC. Co-immunoprecipitation (BTK with Fas), functional apoptosis assays (radiation, Fas ligation), STAT-3 activity measurement Biochemical pharmacology Medium 9751072
2002 Endogenous Btk and Akt physically interact in B cells (DT40 chicken B cells and human Nalm6 B cells) and this interaction is inducible by H2O2 stimulation. PI3K and Btk are involved in Akt phosphorylation following H2O2. Btk and Akt co-localize in the perinuclear region and membrane ruffles in COS-7 cells. Btk positively modulates both ERK and JNK phosphorylation downstream of PI3K. Co-immunoprecipitation of endogenous proteins, immunofluorescence co-localization, kinase phosphorylation assays, PI3K inhibitor studies Biochemical and biophysical research communications Medium 12054657
2012 Btk is required for NK cell activation: Btk-deficient murine NK cells have decreased innate immune responses to the TLR3 ligand poly(I:C), with reduced IFN-γ, perforin, and granzyme-B expression and decreased cytotoxic activity. Btk promotes TLR3-triggered NK cell activation mainly by activating the NF-κB pathway. XLA patients with BTK deficiency also show reduced TLR3-triggered human NK cell activation. Btk-/- mouse NK cell functional assays, NF-κB pathway analysis, Btk inhibitor in vivo administration, adoptive transfer experiments, XLA patient NK cell assays The Journal of biological chemistry High 22589540
2016 BTK transcriptionally upregulates BCL2 expression in mantle cell lymphoma through canonical NF-κB activation. BTK knockdown (by shRNA) downregulates a set of anti-apoptotic and proliferative genes including BCL2, BCL-XL, DAD1, BCL6, MYC, PIK3CA, and BAFF-R, as confirmed by RNA-seq analysis. BTK shRNA knockdown, RNA-seq, NF-κB reporter assays, tissue microarray correlation, in vitro and in vivo drug combination studies Oncogene Medium 27157620
2016 BTK is a novel modulator of p53: BTK is induced in response to DNA damage and p53 activation, and BTK induction leads to p53 phosphorylation, establishing a positive feedback loop that increases p53 protein levels and enhances transactivation of p53 target genes. Inhibiting BTK reduced p53-dependent senescence and apoptosis. BTK induction by DNA damage, BTK inhibitor treatment, p53 phosphorylation assays, senescence and apoptosis functional assays, gene expression analysis Cancer research Medium 27630139
2021 BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues on NLRP3 upon inflammasome activation (demonstrated in vitro and in vivo). BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, likely through charge neutralization upon modification of a polybasic linker that directs NLRP3 Golgi association. BTK-mediated NLRP3 tyrosine phosphorylation positively regulates IL-1β release. Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation assay, NLRP3 localization studies, inflammasome assembly assays (ASC polymerization, oligomerization), IL-1β release measurement The Journal of experimental medicine High 34554188
2021 Low concentrations of BTK inhibitor ibrutinib (and acalabrutinib) selectively block CLEC-2-mediated platelet activation and tyrosine phosphorylation (including Syk and PLCγ2) in human platelets. BTK-deficient XLA patients also show abolished CLEC-2-mediated platelet activation. In contrast, GPVI-mediated platelet responses are only delayed (not abolished) at low inhibitor concentrations, with Syk phosphorylation preserved. This differential reflects a positive feedback role for Btk (along with ADP and thromboxane A2 via P2Y12 and TP receptors) that is present in CLEC-2 but not GPVI signaling in human platelets. Platelet activation assays (aggregation, tyrosine phosphorylation), BTK inhibitor dose-response studies, XLA patient platelet studies, in vivo thrombosis models in mice Haematologica High 31949019
2022 Kinase-dead BTK mutations C481F and C481Y confer ibrutinib resistance through a kinase-independent scaffold mechanism: upon BCR activation, BTK C481F/Y is phosphorylated at Y551 by Src family kinases, which then recruits HCK via its SH2 domain. Structural modeling suggests this binding disrupts an intramolecular autoinhibitory interaction in HCK, activating it. Activated HCK then phosphorylates PLCγ2, propagating BCR signaling and promoting clonogenic cell proliferation despite absence of BTK kinase activity. In vitro kinase assays (confirming loss of kinase activity), structural modeling, co-immunoprecipitation (BTK C481F/Y with HCK), phosphorylation assays (Y551, PLCγ2, NF-κB), clonogenic proliferation assays Science signaling High 35639855
2024 Certain drug-resistant BTK mutations (including kinase-impaired forms) acquire novel protein-protein interactions that sustain BCR signaling independently of BTK enzymatic activity (oncogenic scaffold function). The BTK/IKZF1/3 degrader NX-2127 can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of CLL patients with NX-2127 achieves >80% degradation of BTK. Enzymatic activity characterization of mutant BTK, protein-protein interaction studies, proteasomal degradation assays, BCR signaling blockade assays, clinical BTK degradation measurement Science (New York, N.Y.) High 38301010
2023 Pirtobrutinib, a noncovalent BTK inhibitor, binds BTK with an extensive network of interactions to BTK and water molecules in the ATP-binding region with no direct interaction with C481, inhibiting both BTK and BTK C481 substitution mutants with similar potencies. Pirtobrutinib stabilizes BTK in a closed, inactive conformation (higher melting temperature than covalent BTKi-bound BTK in differential scanning fluorimetry) and prevents Y551 phosphorylation in the activation loop, unlike covalent BTKis. Structural studies (binding mode characterization), enzymatic assays, cell-based assays, differential scanning fluorimetry, Y551 phosphorylation assays, xenograft tumor growth studies Blood High 36796019
2024 BTK is activated in human neutrophils upon fungal (Aspergillus) exposure in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impaired neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function without affecting recruitment or lifespan. BTK activation assays in human neutrophils, BTK inhibitor studies, XLA patient neutrophil studies, neutrophil-specific Btk conditional knockout mice, p40phox and RAC2 activation assays, oxidative burst measurements, in vivo aspergillosis models The Journal of clinical investigation High 38696257
2021 In diffuse large B-cell lymphoma, acquired resistance to BTK inhibitor ibrutinib is epigenetically driven (in part by transcription factor TCF4), causing a phenotypic shift where GTPase RAC2 substitutes for BTK in the activation of PLCγ2 to sustain NF-κB activity. This RAC2-PLCγ2 interaction was also increased in CLL cells from patients with persistent or progressive disease on BTK inhibitor treatment. Ibrutinib resistance modeling in ABC-DLBCL cells, RNAi/genetic screens, RAC2 overexpression, PLCγ2 interaction studies, NF-κB reporter assays, patient CLL cell analysis Blood cancer discovery Medium 34778802
2020 Ternary complex structures of BTK with the E3 ubiquitin ligase cIAP1 and bifunctional degrader compounds were characterized. Increased ternary complex stability or rigidity does not always correlate with increased degradation efficiency. Biochemical, biophysical, and structural studies (X-ray crystallography of ternary complexes), degradation efficiency assays Nature chemical biology High 33199914
2024 TREM2 interacts with the phosphatase SHP1 to inhibit BTK-mediated fatty acid oxidation (FAO) in macrophages during sepsis. TREM2 deficiency in macrophages led to enhanced BTK-mediated FAO, reduced triglyceride accumulation, and improved sepsis outcomes; blockade of FAO abolished these protective effects. Co-immunoprecipitation (TREM2 with SHP1), Trem2 knockout mice, FAO rate measurement, triglyceride accumulation assays, BTK activity assays, survival studies The Journal of clinical investigation Medium 39405126
2003 BTK activates phosphatidylinositol-4-phosphate 5-kinase (PIP5K) downstream of BCR signaling, generating PI(4,5)P2 which serves as substrate for both PI3K and PLCγ, creating a positive feedback loop that amplifies BTK's signal. Review/commentary citing experimental data (Saito et al.) showing BTK-PIP5K activation and PI(4,5)P2 generation Immunity Low 14614849

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine 1359 23782157
1995 Defective B cell development and function in Btk-deficient mice. Immunity 601 7552994
2017 BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 420 28418267
2009 Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunological reviews 402 19290921
2019 Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. The New England journal of medicine 252 31075187
2021 Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Frontiers in cell and developmental biology 211 33777941
2016 Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. Journal of hematology & oncology 194 26957112
2013 Ibrutinib and novel BTK inhibitors in clinical development. Journal of hematology & oncology 188 23958373
2003 The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. The Journal of experimental medicine 187 14610042
2023 Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. The New England journal of medicine 182 37407001
2012 Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. International reviews of immunology 178 22449073
1998 Btk function in B cell development and response. Seminars in immunology 154 9695187
2024 Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science (New York, N.Y.) 119 38301010
2022 Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia. The New England journal of medicine 119 35417637
2014 miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. International journal of oncology 118 24603851
2001 BLNK mediates Syk-dependent Btk activation. Proceedings of the National Academy of Sciences of the United States of America 115 11226282
2021 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 113 34803999
2016 BTK Signaling in B Cell Differentiation and Autoimmunity. Current topics in microbiology and immunology 113 26341110
2019 Targeting BTK in CLL: Beyond Ibrutinib. Current hematologic malignancy reports 112 31028669
2023 Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood 110 36796019
2017 Bruton's tyrosine kinase (BTK) as a promising target in solid tumors. Cancer treatment reviews 105 28641100
1995 The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function. Seminars in immunology 95 8520028
2015 Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate. eLife 93 25699547
1998 Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics 90 9445504
2020 Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nature chemical biology 88 33199914
2014 Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Current hematologic malignancy reports 83 24357428
2021 BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects. Frontiers in immunology 76 34276674
2016 Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms. Pharmacological research 76 27641927
2024 BTK inhibitors in CLL: second-generation drugs and beyond. Blood advances 75 38478390
2023 Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance. Blood advances 70 36287227
2021 BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity. The Journal of experimental medicine 69 34554188
1998 Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. Biochemical pharmacology 69 9751072
2023 BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood advances 67 36696464
2012 Tyrosine kinase Btk is required for NK cell activation. The Journal of biological chemistry 63 22589540
2023 BTK signaling-a crucial link in the pathophysiology of chronic spontaneous urticaria. The Journal of allergy and clinical immunology 61 38141832
2017 Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leukemia & lymphoma 60 28901789
2016 FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene 60 27157620
1996 X-linked agammaglobulinemia (XLA): a genetic tyrosine kinase (Btk) disease. BioEssays : news and reviews in molecular, cellular and developmental biology 60 8885720
1997 Role of Btk in B cell development and signaling. Current opinion in immunology 58 9287186
2021 Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. Frontiers in immunology 54 34349760
2021 Overcoming Acquired Epigenetic Resistance to BTK Inhibitors. Blood cancer discovery 54 34778802
2021 Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): Current development. European journal of medicinal chemistry 52 33740548
2021 Low-dose Btk inhibitors selectively block platelet activation by CLEC-2. Haematologica 50 31949019
2019 Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018). Expert opinion on therapeutic patents 50 30888232
2020 A Fast and Clean BTK Inhibitor. Journal of medicinal chemistry 49 32401033
2016 BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses. Cancer research 48 27630139
2016 From identification of the BTK kinase to effective management of leukemia. Oncogene 48 27669440
2021 Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective. International journal of molecular sciences 47 34299259
2021 The Development of BTK Inhibitors: A Five-Year Update. Molecules (Basel, Switzerland) 47 34885993
1999 Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 46 10075013
2019 Development of BTK inhibitors for the treatment of B-cell malignancies. Archives of pharmacal research 44 30706214
2016 Btk inhibition treats TLR7/IFN driven murine lupus. Clinical immunology (Orlando, Fla.) 43 26821304
2000 Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). Frontiers in bioscience : a journal and virtual library 42 11102316
2024 BTK inhibitors: past, present, and future. Trends in pharmacological sciences 40 39025681
2022 Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK. Science signaling 40 35639855
2021 Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry. Bioorganic & medicinal chemistry 36 34091303
2021 Discovery of novel BTK PROTACs for B-Cell lymphomas. European journal of medicinal chemistry 36 34509879
1999 Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. FEBS letters 36 10561498
2011 TEC family kinases in health and disease--loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK. The FEBS journal 35 21518255
2021 The resistance mechanisms and treatment strategies of BTK inhibitors in B-cell lymphoma. Hematological oncology 34 34651869
2022 Managing Waldenström's macroglobulinemia with BTK inhibitors. Leukemia 33 36402930
2022 Discovery of a potent BTK and IKZF1/3 triple degrader through reversible covalent BTK PROTAC development. Current research in chemical biology 33 36712232
2000 The cellular phenotype conditions Btk for cell survival or apoptosis signaling. Immunological reviews 33 11213806
2024 BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair. Acta neuropathologica 32 38656399
2023 Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma. The Journal of clinical investigation 32 36719376
2021 Targeting the NLRP3 Inflammasome via BTK. Frontiers in cell and developmental biology 32 33718366
2002 XLA patients with BTK splice-site mutations produce low levels of wild-type BTK transcripts. Journal of clinical immunology 31 12405164
2022 Rutin Inhibits Ox-LDL-Mediated Macrophage Inflammation and Foam Cell Formation by Inducing Autophagy and Modulating PI3K/ATK Signaling. Molecules (Basel, Switzerland) 30 35807447
2024 Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms. International journal of molecular sciences 29 38542207
2021 COVID-19 and X-linked agammaglobulinemia (XLA) - insights from a monogenic antibody deficiency. Current opinion in allergy and clinical immunology 29 34596095
2019 Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs? Thrombosis and haemostasis 29 31087308
2010 TLR signaling and effector functions are intact in XLA neutrophils. Clinical immunology (Orlando, Fla.) 29 20634142
2024 BTK drives neutrophil activation for sterilizing antifungal immunity. The Journal of clinical investigation 28 38696257
2024 Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia. Leukemia 28 39048721
2002 Interaction of Btk and Akt in B cell signaling. Biochemical and biophysical research communications 28 12054657
2024 Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. Drugs in R&D 27 38965189
2022 Cardiotoxicity of BTK inhibitors: ibrutinib and beyond. Expert review of hematology 27 35437106
2019 Effects of BTK signalling in pathogenic microorganism infections. Journal of cellular and molecular medicine 27 31397086
2019 Long Non-Coding RNA HOTAIR Modulates KLF12 to Regulate Gastric Cancer Progression via PI3K/ATK Signaling Pathway by Sponging miR-618. OncoTargets and therapy 25 31819516
2023 Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL). Genes 24 38137005
2020 BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy. Journal of leukocyte biology 24 32640487
2018 TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway. Neoplasma 24 30509085
2022 Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors. Journal of personalized medicine 23 35330376
2019 Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption. Bone reports 23 30956999
2024 How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia. Blood 21 38211337
2021 MARCKS affects cell motility and response to BTK inhibitors in CLL. Blood 21 33735912
2024 New Means and Challenges in the Targeting of BTK. Clinical cancer research : an official journal of the American Association for Cancer Research 20 38578606
2024 Bruton's tyrosine kinase (BTK) inhibitors for the treatment of primary central nervous system lymphoma (PCNSL): current progress and latest advances. Leukemia & lymphoma 20 38597202
2021 Targeting Solid Tumors With BTK Inhibitors. Frontiers in cell and developmental biology 20 33937249
2024 TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis. The Journal of clinical investigation 19 39405126
2022 BRUIN MCL-321: phase III study of pirtobrutinib versus investigator choice of BTK inhibitor in BTK inhibitor naive mantle cell lymphoma. Future oncology (London, England) 19 36377973
2004 Therapeutic potential of inhibiting Bruton's tyrosine kinase, (BTK). Current pharmaceutical design 19 15180538
2025 Novel mechanisms of resistance in CLL: variant BTK mutations in second-generation and noncovalent BTK inhibitors. Blood 18 39808800
2021 Current and novel BTK inhibitors in Waldenström's macroglobulinemia. Therapeutic advances in hematology 18 33613931
2020 ROR2 knockdown suppresses breast cancer growth through PI3K/ATK signaling. Aging 18 32614787
2019 Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors. Bioorganic & medicinal chemistry 18 31843459
2003 Amplifying Btk's signal. Immunity 18 14614849
1997 BTK, the tyrosine kinase affected in X-linked agammaglobulinemia. Frontiers in bioscience : a journal and virtual library 18 9159207
2025 BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL. Cancers 17 39941922
2021 BTK Inhibitors in Chronic Lymphocytic Leukemia. Current hematologic malignancy reports 17 34599723

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