Kinase that plays a role in B cell development From Wikipedia, the free encyclopedia
Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTKgene in humans. BTK plays a crucial role in B cell development.
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.
Involvement of BTK in B cell receptor signaling
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.[6] It also has a role in mast cell activation through the high-affinity IgEreceptor.[7]
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.
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]
X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
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
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
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
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
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
Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF (March 2004). "The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations". Cellular Immunology. 228 (1): 42–53. doi:10.1016/j.cellimm.2004.03.004. PMID15203319.
Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, etal. (October 1999). "Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling". Blood. 94 (7): 2357–2364. doi:10.1182/blood.V94.7.2357.419k40_2357_2364. PMID10498607. S2CID21014231.
Matsushita M, Yamadori T, Kato S, Takemoto Y, Inazawa J, Baba Y, etal. (April 1998). "Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK)". Biochemical and Biophysical Research Communications. 245 (2): 337–343. doi:10.1006/bbrc.1998.8420. PMID9571151.
Carpenter CL (April 2004). "Btk-dependent regulation of phosphoinositide synthesis". Biochemical Society Transactions. 32 (Pt 2): 326–329. doi:10.1042/BST0320326. PMID15046600. S2CID41318916.
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. doi:10.1016/j.smim.2005.10.002. PMID16300960.