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Bruton's tyrosine kinase

(Redirected from BTK inhibitor)

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.

BTK
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBTK, AGMX1, AT, ATK, BPK, IMD1, PSCTK1, XLA, Bruton tyrosine kinase, IGHD3
External IDsOMIM: 300300; MGI: 88216; HomoloGene: 30953; GeneCards: BTK; OMA:BTK - orthologs
Orthologs
SpeciesHumanMouse
Entrez

695

12229

Ensembl

ENSG00000010671

ENSMUSG00000031264

UniProt

Q06187

P35991

RefSeq (mRNA)

NM_001287345
NM_000061
NM_001287344

NM_013482

RefSeq (protein)

NP_000052
NP_001274273
NP_001274274

NP_038510

Location (UCSC)Chr X: 101.35 – 101.39 MbChr X: 133.44 – 133.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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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

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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 IgE receptor.[7]

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.[8]

Clinical significance

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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 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).[12] As BTK is also linked to autoimmune disorders,[13][14] 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).[15]

BTK inhibitors

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Approved drugs that inhibit BTK:

Various drugs that inhibit BTK are in clinical trials:[24]

Discovery

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Bruton's tyrosine kinase is named for Ogden Bruton, who first described XLA in 1952.[10][40] 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.[41][42][43]

Interactions

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Bruton's tyrosine kinase has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000010671 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031264 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Pal Singh S, Dammeijer F, Hendriks RW (February 2018). "Role of Bruton's tyrosine kinase in B cells and malignancies". Molecular Cancer. 17 (1): 57. doi:10.1186/s12943-018-0779-z. PMC 5817726. PMID 29455639.
  6. ^ Owen JA, Punt J, Stranford SA, Jones PP (2013). Kuby Immunology (7th ed.). New York: W.H. Freeman. p. 93. ISBN 978-14641-3784-6.
  7. ^ Turner H, Kinet JP (November 1999). "Signalling through the high-affinity IgE receptor Fc epsilonRI". Nature. 402 (6760 Suppl): B24–B30. doi:10.1038/35037021. PMID 10586892.
  8. ^ Lowe J, Joseph RE, Andreotti AH (1 January 2022). "Conformational switches that control the TEC kinase - PLCγ signaling axis". Journal of Structural Biology. 6: 100061. doi:10.1016/j.yjsbx.2022.100061. PMC 8803661. PMID 35128378.
  9. ^ Geier CB, Sauerwein KM, Leiss-Piller A, Zmek I, Fischer MB, Eibl MM, et al. (18 August 2018). "Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis". Frontiers in Immunology. 9: 2984. doi:10.3389/fimmu.2018.02984. PMC 6305442. PMID 30619340.
  10. ^ a b X-Linked Agammaglobulinemia Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation.
  11. ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
  12. ^ Pal Singh S, Dammeijer F, Hendriks RW (December 2018). "Role of Bruton's tyrosine kinase in B cells and malignancies". Molecular Cancer. 17 (1): 57. doi:10.1186/s12943-018-0779-z. ISSN 1476-4598. PMC 5817726. PMID 29455639.
  13. ^ Corneth OB, de Bruijn MJ, Rip J, Asmawidjaja PS, Kil LP, Hendriks RW (1 July 2016). "Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis". The Journal of Immunology. 197 (1): 58–67. doi:10.4049/jimmunol.1600208. ISSN 0022-1767. PMID 27226091.
  14. ^ Rip J, de Bruijn MJ, Appelman MK, Pal Singh S, Hendriks RW, Corneth OB (2019). "Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease". Frontiers in Immunology. 10: 95. doi:10.3389/fimmu.2019.00095. ISSN 1664-3224. PMC 6363707. PMID 30761150.
  15. ^ Krämer J, Bar-Or A, Turner TJ, Wiendl H (May 2023). "Bruton tyrosine kinase inhibitors for multiple sclerosis". Nature Reviews Neurology. 19 (5): 289–304. doi:10.1038/s41582-023-00800-7. ISSN 1759-4758. PMC 10100639. PMID 37055617.
  16. ^ "FDA approves new treatment for adults with mantle cell lymphoma". Food and Drug Administration. 24 March 2020.
  17. ^ "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.
  18. ^ BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
  19. ^ "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.
  20. ^ Dhillon S (June 2020). "Tirabrutinib: First Approval". Drugs. 80 (8): 835–840. doi:10.1007/s40265-020-01318-8. PMID 32382949. S2CID 218531327.
  21. ^ "FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma". U.S. Food and Drug Administration (FDA). 27 January 2023.
  22. ^ Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, et al. (March 2021). "Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study". Lancet. 397 (10277): 892–901. doi:10.1016/S0140-6736(21)00224-5. PMID 33676628. S2CID 232116910.
  23. ^ Dhillon S (2021). "Orelabrutinib: First Approval". Drugs. 81 (4): 503–507. doi:10.1007/s40265-021-01482-5. PMID 33704654.
  24. ^ Alu A, Lei H, Han X, Wei Y, Wei X (October 2022). "BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies". Journal of Hematology & Oncology. 15 (1): 138. doi:10.1186/s13045-022-01353-w. PMC 9526392. PMID 36183125.
  25. ^ Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, et al. (June 2019). "Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis". The New England Journal of Medicine. 380 (25): 2406–2417. doi:10.1056/NEJMoa1901981. PMID 31075187.
  26. ^ Clinical trial number NCT02975349 for "A Study of Efficacy and Safety of M2951 in Subjects With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
  27. ^ 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
  28. ^ Dolgin E (January 2021). "BTK blockers make headway in multiple sclerosis". Nature Biotechnology. 39 (1): 3–5. doi:10.1038/s41587-020-00790-7. PMID 33432223.
  29. ^ 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
  30. ^ Wexler M (21 June 2022). "Remibrutinib for Multiple Sclerosis". BioNews, Inc.
  31. ^ "Genentech: Our Pipeline". www.gene.com. Retrieved 5 June 2023.
  32. ^ 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
  33. ^ 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
  34. ^ "Genentech: Our Pipeline". www.gene.com. Retrieved 10 October 2020.
  35. ^ 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
  36. ^ "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 5 April 2016. Retrieved 22 March 2016.
  37. ^ 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
  38. ^ Garde D (19 March 2015). "Lilly inks a $690M deal to get its hands on an autoimmune drug". FierceBiotech.
  39. ^ Rice WG, Howell SB, Zhang H, Rastgoo N, Local A, Kurtz SE, et al. (July 2022). "Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia". Molecular Cancer Therapeutics. 21 (7): 1125–1135. doi:10.1158/1535-7163.MCT-21-0832. PMC 9256809. PMID 35499387.
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  41. ^ Vetrie D, Vořechovský I, Sideras P, Holland J, Davies A, Flinter F, et al. (21 January 1993). "The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases". Nature. 361 (6409): 226–233. Bibcode:1993Natur.361..226V. doi:10.1038/361226a0. ISSN 0028-0836. PMID 8380905.
  42. ^ Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen R, Klisak I, et al. (January 1993). "Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia". Cell. 72 (2): 279–290. doi:10.1016/0092-8674(93)90667-F. PMID 8425221.
  43. ^ Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. (15 January 1994). "Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells". Journal of Immunology. 152 (2): 557–565. doi:10.4049/jimmunol.152.2.557. ISSN 0022-1767. PMID 8283037.
  44. ^ 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. PMID 15203319.
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Further reading

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