Bruton's tyrosine kinase
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Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.
Structure
BTK contains five different protein interaction domains. These domains include an amino terminal pleckstrin homology (PH) domain, a proline-rich TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, as well as a protein kinase domain with tyrosine phosphorylation activity.[1]
Part of the TH domain is folded against the PH domain while the rest is intrinsically disordered.
Function
BTK plays a crucial role in B cell development as it is required for transmitting signals from the pre-B cell receptor that forms after successful immunoglobulin heavy chain rearrangement.[2] It also has a role in mast cell activation through the high-affinity IgE receptor.[3]
BTK contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces BTK to phosphorylate phospholipase C (PLC), which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.[4]
Clinical significance
Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA and selective IgM deficiency.[5] Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The BTK gene is located on the X chromosome (Xq21.3-q22).[6] At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.[7]
BTK is important for the survival and proliferation of leukemic B cells, which motivated efforts to develop BTK inhibitors as treatments for B cell malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).[8] As BTK is also linked to autoimmune disorders,[9][10] recent efforts have sought to evaluate BTK inhibition as a therapeutic strategy for treatment of diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA).[11]
BTK inhibitors
Approved drugs that inhibit BTK:
- Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
- Acalabrutinib (Calquence), approved in October 2017[12] for relapsed mantle cell lymphoma and in October 2019 for Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL)
- Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).[13] It can be taken by mouth.[14][15]
- Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma.[16]
- Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma.[17][18]
- Orelabrutinib, approved in China for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past.[19]
Various drugs that inhibit BTK are in clinical trials:[20]
- Phase 3:
- Evobrutinib for multiple sclerosis.[21][22][23]
- Tolebrutinib, for multiple sclerosis.[24][25]
- Remibrutinib, for multiple sclerosis.[26]
- Fenebrutinib (RG7845) for multiple sclerosis.[27][28]
- Rilzabrutinib
- Phase 2:
- ABBV-105 for systemic lupus erythematosus (SLE)[29]
- Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.[30]
- Phase 1:
- Tirabrutinib, for non-Hodgkin lymphoma and/or CLL.[31] Renamed GS-4059 and now in trial NCT02457598.[32]
- Spebrutinib (AVL-292, CC-292) [33]
- HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015[34]
- Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma, acute myeloid leukaemia, and myelodysplastic syndromes (Phase I Trial; Phase I Trial). The inhibitor targets multiple kinase pathways, including BTK and FLT3.[35]
- Elsubrutinib
- Vecabrutinib
- Nemtabrutinib
Discovery
Bruton's tyrosine kinase is named for Ogden Bruton, who first described XLA in 1952.[6][36] Later studies in 1993 and 1994 reported the discovery of BTK (initially termed B cell progenitor kinase or BPK) and found that BTK levels are reduced in B cells from XLA patients.[37][38][39]
Interactions
Bruton's tyrosine kinase has been shown to interact with:
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References
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- ↑ a b X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
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- ↑ BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
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- ↑ Clinical trial number NCT02975349 for "A Study of Efficacy and Safety of M2951 in Subjects With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
- ↑ Clinical trial number NCT04032171 for "A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With an Interferon Beta 1a (Avonex®), in Participants With RMS to Evaluate Efficacy and Safety " at ClinicalTrials.gov
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- ↑ Clinical trial number NCT04742400 for "A Phase 2 Clinical Trial of Tolebrutinib, a Brain-penetrant Bruton s Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis" at ClinicalTrials.gov
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- ↑ Clinical trial number NCT04544449 for "A Phase III Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Patients With Primary Progressive Multiple Sclerosis" at ClinicalTrials.gov
- ↑ Clinical trial number NCT03978520 for "A Study to Investigate the Safety and Efficacy of ABBV-105 and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus - Full Text View - ClinicalTrials.gov" at ClinicalTrials.gov
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- ↑ Clinical trial number NCT01659255 for "ONO-4059 Phase I Dose-escalation Study to Investigate the Safety and Tolerability of ONO-4059 Given as Monotherapy in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma and/or Chronic Lymphocytic Leukaemi" at ClinicalTrials.gov
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- ↑ Clinical trial number NCT01351935 for "Escalating Dose Study in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia" at ClinicalTrials.gov
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Further reading
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External links
- GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
- Template:Replace at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Template:UCSC gene info
- Template:PDBe-KB2
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