Bruton's tyrosine kinase
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| Location (UCSC) | Chr X: 101.35 – 101.39 Mb | Chr X: 133.44 – 133.48 Mb | |||||||
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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.[5]
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
Btk contains a PH domain that binds
diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.[8]
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.[9] 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).[10] At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.[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)
- 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]
- 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]
- 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]
- 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]
Discovery
Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.[10]
Interactions
Bruton's tyrosine kinase has been shown to
interact
with:
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000010671 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031264 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 29455639.
- ISBN 978-14641-3784-6.
- PMID 10586892.
- PMID 35128378.
- PMID 30619340.
- ^ a b X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
- PMID 31819097.
- ^ "FDA approves new treatment for adults with mantle cell lymphoma". Food and Drug Administration. 24 March 2020.
- ^ "FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage". U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019.
- ^ BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
- ^ "FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma". U.S. Food and Drug Administration (FDA). 19 January 2023. Retrieved 26 January 2023.
- S2CID 218531327.
- ^ "FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma". U.S. Food and Drug Administration (FDA). 27 January 2023.
- S2CID 232116910.
- .
- PMID 36183125.
- PMID 31075187.
- ^ 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
- PMID 33432223.
- ^ 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
- ^ Wexler M (21 June 2022). "Remibrutinib for Multiple Sclerosis". BioNews, Inc.
- ^ "Genentech: Our Pipeline". www.gene.com. Retrieved 5 June 2023.
- ^ 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
- ^ "Genentech: Our Pipeline". www.gene.com. Retrieved 10 October 2020.
- ^ 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
- ^ "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 5 April 2016. Retrieved 22 March 2016.
- ^ 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
- ^ Garde D (19 March 2015). "Lilly inks a $690M deal to get its hands on an autoimmune drug". FierceBiotech.
- PMID 35499387.
- PMID 15203319.
- ^ PMID 12093870.
- S2CID 21014231.
- PMID 11751885.
- PMID 9770463.
- PMID 14623887.
- PMID 10373551.
- PMID 9012831.
- PMID 10981967.
- S2CID 86153017.
- PMID 9571151.
- PMID 10339589.
Further reading
- Ochs HD, Aruffo A (December 1993). "Advances in X-linked immunodeficiency diseases". Current Opinion in Pediatrics. 5 (6): 684–691. PMID 7907259.
- Uckun FM (September 1998). "Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis". Biochemical Pharmacology. 56 (6): 683–691. PMID 9751072.
- Tsubata T, Wienands J (2001). "B cell signaling. Introduction". International Reviews of Immunology. 20 (6): 675–678. S2CID 218878743.
- Etzioni A (April 2002). "Novel aspects of hypogammaglobulinemic states". The Israel Medical Association Journal. 4 (4): 294–297. PMID 12001708.
- Niiro H, Clark EA (November 2003). "Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1". Immunity. 19 (5): 637–640. PMID 14614850.
- Carpenter CL (April 2004). "Btk-dependent regulation of phosphoinositide synthesis". Biochemical Society Transactions. 32 (Pt 2): 326–329. S2CID 41318916.
- Hendriks RW, Kersseboom R (February 2006). "Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells". Seminars in Immunology. 18 (1): 67–76. PMID 16300960.
External links
- GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
- Bruton's+tyrosine+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human BTK genome location and BTK gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: Q06187 (Tyrosine-protein kinase BTK) at the PDBe-KB.
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