Targeting Bruton's Tyrosine Kinase (BTK) As a Signaling Pathway in Immune-mediated Diseases: from Molecular Mechanisms to Leading Treatments

Overview

Journal Adv Rheumatol

Publisher Biomed Central

Specialty Rheumatology

Date 2024 Aug 21

PMID 39169436

Authors

Gita Manzari Tavakoli

Niloufar Yazdanpanah

Nima Rezaei

Affiliations

Soon will be listed here.

Abstract

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.

References

Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F . The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993; 361(6409):226-33. DOI: 10.1038/361226a0. View

Szilveszter K, Nemeth T, Mocsai A . Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases. Front Immunol. 2019; 10:1862. PMC: 6697022. DOI: 10.3389/fimmu.2019.01862. View

Rip J, de Bruijn M, Appelman M, Singh S, Hendriks R, Corneth O . Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease. Front Immunol. 2019; 10:95. PMC: 6363707. DOI: 10.3389/fimmu.2019.00095. View

Robak E, Robak T . Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives. J Clin Med. 2022; 11(10). PMC: 9145705. DOI: 10.3390/jcm11102807. View

Hendriks R, Yuvaraj S, Kil L . Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014; 14(4):219-32. DOI: 10.1038/nrc3702. View

Liu L, Di Paolo J, Barbosa J, Rong H, Reif K, Wong H . Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther. 2011; 338(1):154-63. DOI: 10.1124/jpet.111.181545. View

Evans E, Tester R, Aslanian S, Karp R, Sheets M, Labenski M . Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013; 346(2):219-28. DOI: 10.1124/jpet.113.203489. View

Niiro H, Clark E . Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002; 2(12):945-56. DOI: 10.1038/nri955. View

Zarrin A, Bao K, Lupardus P, Vucic D . Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov. 2020; 20(1):39-63. PMC: 7569567. DOI: 10.1038/s41573-020-0082-8. View

10.

McDonald C, Xanthopoulos C, Kostareli E . The role of Bruton's tyrosine kinase in the immune system and disease. Immunology. 2021; 164(4):722-736. PMC: 8561098. DOI: 10.1111/imm.13416. View

11.

Zhang D, Gong H, Meng F . Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases. Molecules. 2021; 26(16). PMC: 8399599. DOI: 10.3390/molecules26164907. View

12.

Buggy J, Elias L . Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012; 31(2):119-32. DOI: 10.3109/08830185.2012.664797. View

13.

Owens T, Brameld K, Verner E, Ton T, Li X, Zhu J . Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib). J Med Chem. 2022; 65(7):5300-5316. DOI: 10.1021/acs.jmedchem.1c01170. View

14.

Li R, Tang H, Burns J, Hopkins B, Le Coz C, Zhang B . BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy. Acta Neuropathol. 2022; 143(4):505-521. PMC: 8960592. DOI: 10.1007/s00401-022-02411-w. View

15.

Fraussen J, Claes N, Van Wijmeersch B, van Horssen J, Stinissen P, Hupperts R . B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses. Clin Immunol. 2016; 173:124-132. DOI: 10.1016/j.clim.2016.10.001. View

16.

Murrell D, Patsatsi A, Stavropoulos P, Baum S, Zeeli T, Kern J . Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study. Br J Dermatol. 2021; 185(4):745-755. PMC: 8518737. DOI: 10.1111/bjd.20431. View

17.

Altman E . Novel Therapies for Pemphigus Vulgaris. Am J Clin Dermatol. 2020; 21(6):765-782. DOI: 10.1007/s40257-020-00544-w. View

18.

Smith P, Krishnarajah J, Nunn P, Hill R, Karr D, Tam D . A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers. Br J Clin Pharmacol. 2017; 83(11):2367-2376. PMC: 5651318. DOI: 10.1111/bcp.13351. View

19.

Goodale E, Varjonen K, Outerbridge C, Bizikova P, Borjesson D, Murrell D . Efficacy of a Bruton's Tyrosine Kinase Inhibitor (PRN-473) in the treatment of canine pemphigus foliaceus. Vet Dermatol. 2020; 31(4):291-e71. DOI: 10.1111/vde.12841. View

20.

Lee A, Sandhu S, Imlay-Gillespie L, Mulligan S, Shumack S . Successful use of Bruton's kinase inhibitor, ibrutinib, to control paraneoplastic pemphigus in a patient with paraneoplastic autoimmune multiorgan syndrome and chronic lymphocytic leukaemia. Australas J Dermatol. 2017; 58(4):e240-e242. DOI: 10.1111/ajd.12615. View