Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms

Duarte, Daniel; Lamontanara, Allan Joaquim; Sala, Giuseppina La; Jeong, Sukyo; Sohn, Youn Soo; Panjkovich, Alejandro; Georgeon, Sandrine; Kükenshöner, Tim; Marcaida, M.J.; Pojer, F.; Vivo, Marco De; Svergun, Dmitri I.; Kim, Kwang Ho; Peraro, Matteo Dal; Hantschel, Oliver

doi:10.1038/s41467-020-16128-5

Cited by 29 publications

(24 citation statements)

References 56 publications

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“…This initiates the formation of a signaling complex comprising further adapter proteins and providing docking sites for phosphatidylinositol (PI) 3-kinase and phospholipase Cγ2 (PLCγ2) [ 18 ]. PI3-kinase activation increases membrane levels of PI 3,4,5-trisphosphate (PIP3) that binds with high affinity to the PH-domain of Btk thereby leading to its translocation to the plasma membrane and complex conformational changes of the enzyme also involving the SH2 domain [ 22 , 23 ]. Lyn and Syk then phosphorylate Btk at Y-551 in the kinase domain, and subsequent autophosphorylation at Y-223 in the SH3 domain completes the activation of Btk [ 18 , 19 , 22 , 24 , 25 ] ( Figure 1 ).…”

Section: Role Of Btk In Platelet Signaling and Platelet Effects Ofmentioning

confidence: 99%

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

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Section: Role Of Btk In Platelet Signaling and Platelet Effects Ofmentioning

confidence: 99%

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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“…The SH2 domain and kinase domain together form an allosteric interface, which has been reported to be critical for the activation of BTK. Interestingly, Duarte et al [7] have recently demonstrated that this interface can contain SH2 mutations in XLA, which dramatically impacts BTK activation. The cysteine residue at position 481 of the kinase domain (C481) of BTK is a region of particular interest due to it being a target of many BTK inhibiting drugs.…”

Section: The Structure Of Btkmentioning

confidence: 99%

The role of Bruton's tyrosine kinase in the immune system and disease

2021

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Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B‐cell biology and function, highlighted by its position as a critical component of the B‐cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID‐19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

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“…Small angle X-ray scattering (SAXS) data suggested quite early that BTK adopts an extended arrangement of its domains ( Márquez et al, 2003 ), however, the functional state that this extended conformational state reflects is unclear. More recent work has demonstrated that a BTK SH2 specific binding protein abrogates the kinase activity of BTK by blocking a predicted SH2/kinase domain interface required for activation ( Duarte et al, 2020 ; Jeong et al, 2020 ). The interface between SH2 and kinase domains in TEC family and other tyrosine kinases is known to play a critical role in enhancing kinase activity beyond the isolated kinase domain ( Nagar et al, 2003 ; Joseph et al, 2007 ; Filippakopoulos et al, 2008 ; Lamontanara et al, 2014 ).…”

Section: Sh3 and Sh2 Domains Influence The Kinase Domain Regulatory Apparatusmentioning

confidence: 99%

Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

Kueffer

Joseph

Andreotti

2021

Front. Cell Dev. Biol.

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Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.

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Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms

Cited by 29 publications

References 56 publications

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

The role of Bruton's tyrosine kinase in the immune system and disease

Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

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