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Review
. 2021 Sep 27;10(10):2560.
doi: 10.3390/cells10102560.

Bruton's Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Antonio García-Merino  1
Affiliations
Review

Bruton's Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Antonio García-Merino. Cells. .

Abstract

B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton's tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials.

Keywords: B cells; BTK inhibitors; Bruton’s tyrosine kinase; multiple sclerosis.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the 659 amino acid BTK structure. BTK has five domains. The pleckstrin homology domain (PH) has phospholipid binding ability, which allows for the recruitment of BTK from the cytosol to the plasma membrane. The Tec homology domain (TH) plays an essential role in BTK stabilization. The Src domains (SH3 and SH2) are involved in protein–protein interactions. The kinase domain is the catalytic part of the protein. Each domain interacts with different signaling molecules. * Indicates the cysteine-481 residue position in the kinase domain, which is the site for covalent binding of the BTK irreversible inhibitors.
Figure 2
Figure 2
Schematic representation of role of BTK in signaling after antigen binding to the B cell receptor (BCR). Antigen binding triggers a cascade of signaling events, which leads to BTK translocation from the cytosol to the cell membrane through their union to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). BTK phosphorylates phospholipase C gamma 2 (PLCγ2), cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), and generates two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). This activates pathways, leading to the nuclear factor of activated T cells (NFAT) and nuclear factor kappa B (NFkB). (Figure taken from Román-García [43], with permission).
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