Bruton's tyrosine kinase explained

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, 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 inhibitors

Approved drugs that inhibit BTK:

• Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
• Acalabrutinib (Calquence), approved in October 2017^[8] 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).^[9] It can be taken by mouth.^{[10] [11]}
• Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma.^[12]
• Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma.^{[13] [14]}
• 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.^[15]

Various drugs that inhibit BTK are in clinical trials:^[16]

• Phase 3:
  • Evobrutinib for multiple sclerosis.^[17]
  • Tolebrutinib, for multiple sclerosis.^[18]
  • Remibrutinib, for multiple sclerosis.^[19]
  • Fenebrutinib (RG7845) for multiple sclerosis.^[20]
• Phase 2:
  • ABBV-105 for systemic lupus erythematosus (SLE)
  • Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.^[21]
• Phase 1:
  • Tirabrutinib, for non-Hodgkin lymphoma and/or CLL. Renamed GS-4059 and now in trial NCT02457598.^[22]
  • Spebrutinib (AVL-292, CC-292)
  • HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015^[23]
  • 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.^[24]

Discovery

Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952.^[6]

Interactions

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

• ARID3A^[25]
• BLNK (SLP-65),^[26]
• CAV1,^[27]
• GNAQ,^[28]
• GTF2I,^{[29] [30] [31]}
• PLCG2,^{[32] [33]}
• PRKD1,^[34] and
• SH3BP5.^{[35] [36]}

Further reading

• Ochs HD, Aruffo A . Advances in X-linked immunodeficiency diseases . Current Opinion in Pediatrics . 5 . 6 . 684–691 . December 1993 . 7907259 . 10.1097/00008480-199312000-00008 .
• Uckun FM . Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis . Biochemical Pharmacology . 56 . 6 . 683–691 . September 1998 . 9751072 . 10.1016/S0006-2952(98)00122-1 .
• Tsubata T, Wienands J . B cell signaling. Introduction . International Reviews of Immunology . 20 . 6 . 675–678 . 2001 . 11913944 . 10.3109/08830180109045584 . 218878743 .
• Etzioni A . Novel aspects of hypogammaglobulinemic states . The Israel Medical Association Journal . 4 . 4 . 294–297 . April 2002 . 12001708 .
• Niiro H, Clark EA . Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1 . Immunity . 19 . 5 . 637–640 . November 2003 . 14614850 . 10.1016/S1074-7613(03)00303-0 . free .
• Carpenter CL . Btk-dependent regulation of phosphoinositide synthesis . Biochemical Society Transactions . 32 . Pt 2 . 326–329 . April 2004 . 15046600 . 10.1042/BST0320326 . 41318916 .
• Hendriks RW, Kersseboom R . Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells . Seminars in Immunology . 18 . 1 . 67–76 . February 2006 . 16300960 . 10.1016/j.smim.2005.10.002 .

External links

• GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia

Notes and References

1. Pal Singh S, Dammeijer F, Hendriks RW . Role of Bruton's tyrosine kinase in B cells and malignancies . Molecular Cancer . 17 . 1 . 57 . February 2018 . 29455639 . 5817726 . 10.1186/s12943-018-0779-z . free .
2. Book: Owen JA, Punt J, Stranford SA, Jones PP . Kuby Immunology . 2013 . W.H. Freeman . New York . 978-14641-3784-6 . 93 . 7th.
3. Turner H, Kinet JP . Signalling through the high-affinity IgE receptor Fc epsilonRI . Nature . 402 . 6760 Suppl . B24–B30 . November 1999 . 10586892 . 10.1038/35037021 . free .
4. Lowe J, Joseph RE, Andreotti AH . Conformational switches that control the TEC kinase - PLCγ signaling axis . Journal of Structural Biology . 6 . 100061 . 2022-01-01 . 35128378 . 10.1016/j.yjsbx.2022.100061 . 8803661 .
5. Geier CB, Sauerwein KM, Leiss-Piller A, Zmek I, Fischer MB, Eibl MM, Wolf HM . Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis . Frontiers in Immunology . 9 . 2984 . 18 August 2018 . 30619340 . 6305442 . 10.3389/fimmu.2018.02984 . free .
6. http://www.immunedisease.com/US/patients/IDF/agamma.html X-Linked Agammaglobulinemia
7. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4 . 2019NatSR...918577S .
8. Web site: FDA approves new treatment for adults with mantle cell lymphoma. . 24 March 2020.
9. 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) . 14 November 2019 . 15 November 2019.
10. http://www.nasdaq.com/press-release/beigene-announces-initiation-of-a-combination-trial-of-the-btk-inhibitor-bgb3111-with-the-pd1-20160629-00939 BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
11. Web site: FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma . U.S. Food and Drug Administration (FDA) . 19 January 2023 . 26 January 2023.
12. Dhillon S . Tirabrutinib: First Approval . Drugs . 80 . 8 . 835–840 . June 2020 . 32382949 . 10.1007/s40265-020-01318-8 . 218531327 .
13. Web site: 27 January 2023 . FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma . U.S. Food and Drug Administration (FDA) .
14. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M . Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study . Lancet . 397 . 10277 . 892–901 . March 2021 . 33676628 . 10.1016/S0140-6736(21)00224-5 . 232116910 .
15. 10.1007/s40265-021-01482-5 . Orelabrutinib: First Approval . 2021 . Drugs . 81 . 4 . 503–507 . Dhillon S .
16. Alu A, Lei H, Han X, Wei Y, Wei X . BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies . Journal of Hematology & Oncology . 15 . 1 . 138 . October 2022 . 36183125 . 9526392 . 10.1186/s13045-022-01353-w . free .
17. Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS . Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis . The New England Journal of Medicine . 380 . 25 . 2406–2417 . June 2019 . 31075187 . 10.1056/NEJMoa1901981 . free .
18. Dolgin E . BTK blockers make headway in multiple sclerosis . Nature Biotechnology . 39 . 1 . 3–5 . January 2021 . 33432223 . 10.1038/s41587-020-00790-7 . free .
19. News: Remibrutinib for Multiple Sclerosis . BioNews, Inc. . 21 June 2022 . Wexler M .
20. Web site: Genentech: Our Pipeline . 2023-06-05 . www.gene.com . en-us.
21. Web site: Genentech: Our Pipeline. 10 October 2020. www.gene.com.
22. Web site: Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016 . 22 March 2016 . https://web.archive.org/web/20160405234507/http://global.onclive.com/conference-coverage/hematology-2016/novel-btk-pi3k-inhibitors-on-horizon-for-relapsed-cll . 5 April 2016 . dead .
23. News: Garde D . Lilly inks a $690M deal to get its hands on an autoimmune drug. FierceBiotech. 19 March 2015. en.
24. Rice WG, Howell SB, Zhang H, Rastgoo N, Local A, Kurtz SE, Lo P, Bottomly D, Wilmot B, McWeeney SK, Druker BJ, Tyner JW . Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia . Molecular Cancer Therapeutics . 21 . 7 . 1125–1135 . July 2022 . 35499387 . 9256809 . 10.1158/1535-7163.MCT-21-0832 .
25. Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF . The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations . Cellular Immunology . 228 . 1 . 42–53 . March 2004 . 15203319 . 10.1016/j.cellimm.2004.03.004 .
26. Hashimoto S, Iwamatsu A, Ishiai M, Okawa K, Yamadori T, Matsushita M, Baba Y, Kishimoto T, Kurosaki T, Tsukada S . 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 . October 1999 . 10498607 . 10.1182/blood.V94.7.2357.419k40_2357_2364 . 21014231 .
27. Vargas L, Nore BF, Berglof A, Heinonen JE, Mattsson PT, Smith CI, Mohamed AJ . Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx . The Journal of Biological Chemistry . 277 . 11 . 9351–9357 . March 2002 . 11751885 . 10.1074/jbc.M108537200 . free .
28. Ma YC, Huang XY . Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase . Proceedings of the National Academy of Sciences of the United States of America . 95 . 21 . 12197–12201 . October 1998 . 9770463 . 22808 . 10.1073/pnas.95.21.12197 . free . 1998PNAS...9512197M .
29. Sacristán C, Tussié-Luna MI, Logan SM, Roy AL . Mechanism of Bruton's tyrosine kinase-mediated recruitment and regulation of TFII-I . The Journal of Biological Chemistry . 279 . 8 . 7147–7158 . February 2004 . 14623887 . 10.1074/jbc.M303724200 . free .
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31. Yang W, Desiderio S . BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement . Proceedings of the National Academy of Sciences of the United States of America . 94 . 2 . 604–609 . January 1997 . 9012831 . 19560 . 10.1073/pnas.94.2.604 . free . 1997PNAS...94..604Y .
32. Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, Kurosaki T, Yamamoto T . Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells . The Journal of Experimental Medicine . 196 . 1 . 51–63 . July 2002 . 12093870 . 2194016 . 10.1084/jem.20020068 .
33. Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ . Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex . Immunity . 13 . 2 . 243–253 . August 2000 . 10981967 . 10.1016/s1074-7613(00)00024-8 . free .
34. Johannes FJ, Hausser A, Storz P, Truckenmüller L, Link G, Kawakami T, Pfizenmaier K . Bruton's tyrosine kinase (Btk) associates with protein kinase C mu . FEBS Letters . 461 . 1–2 . 68–72 . November 1999 . 10561498 . 10.1016/S0014-5793(99)01424-6 . 86153017 .
35. Matsushita M, Yamadori T, Kato S, Takemoto Y, Inazawa J, Baba Y, Hashimoto S, Sekine S, Arai S, Kunikata T, Kurimoto M, Kishimoto T, Tsukada S . 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 . April 1998 . 9571151 . 10.1006/bbrc.1998.8420 .
36. Yamadori T, Baba Y, Matsushita M, Hashimoto S, Kurosaki M, Kurosaki T, Kishimoto T, Tsukada S . Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein . Proceedings of the National Academy of Sciences of the United States of America . 96 . 11 . 6341–6346 . May 1999 . 10339589 . 26883 . 10.1073/pnas.96.11.6341 . free . 1999PNAS...96.6341Y .