Introduction
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Although its etiology is not fully understood yet, genetic, epidemiological, and pathological studies support the hypothesis that autoimmunity plays a major role in disease pathogenesis [1]. Classically, CD4+ T cells have been considered the primary drivers in MS. However, histopathological studies and the success of clinical trials with B-cell-depleting therapies indicate that the general view of MS as a condition meditated only by CD4+ T cells must be reassessed, and the role of CD8+ T cells, B cells, mast cells, and myeloid cells emphasized [2].
Over the past two decades, a significant number of disease-modifying treatments (DMT) have been approved for clinical use in patients with relapsing-remitting MS (RRMS). This has dramatically influenced the management of MS patients in daily practice and has positively influenced prognosis of a subset of patients. Nonetheless, DMT are not specific for MS, and given the heterogeneity of the disease, its use may be limited by intolerance, toxicity, or comorbidities that preclude the persistent use of these compounds. Furthermore, novel-targeted therapies should be studied in refractory patients and patients with progressive forms of the disease. Therefore, there remains an unmet need for new MS treatment.
Tyrosine kinases (TYKs) are intracellular enzymes mediating tyrosine phosphorylation of downstream molecules that participate in specific signaling pathways. Reversible phosphorylation is a major mechanism used by all cells, consequently TYKs have a key role in numerous processes that control cellular proliferation and differentiation, regulate cell growth and cellular metabolism, and promote cell survival as well as apoptosis.
TYK comprise two general classes of molecules: receptor TYKs (RTYKs), and non-receptor TYKs (non-RTYKs [3,4]). The binding of a ligand (cytokine or growth factor) to RTYKs facilitates the dimerization of the receptor, its auto-phosphorylation, and the transfer of the phosphate from ATP to the hydroxyl groups of tyrosine residues on the receptor itself or on substrate proteins, both of which promote signal transduction. Likewise, activation of non-RTYKs, which are intracellular TYKs without a direct role in sensing extracellular cues, also occurs following phosphorylation of tyrosine residues on proteins by kinases, which activates downstream intracellular signaling pathways and cellular effector functions [3,4]. Therefore, given their role in multiple signaling processes and disease pathogenesis TYKs have emerged as excellent therapeutic targets for various diseases, resulting in the development of diverse TYKs inhibitors. Indeed, small molecule TYKs inhibitors have expanded the therapeutic armamentarium in oncology, and more recently in different autoimmune diseases [5]. These inhibitors typically, but not always, bind to the nucleotide-binding pocket of the catalytic domain, and can thereby modulate changes in the conformation of the molecule that are necessary for kinase activation [6].
Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinase, is a cytoplasmic non-RTYKs that transmits signals via a variety of cell-surface molecules and is expressed by all cells of the hematopoietic lineage, except T cells, NK cells, and plasma cells [7]. BTK is also highly expressed by lung tissue, mainly localized in the membrane of alveolar epithelial cells [8].BTK is an essential component of different B cell receptor (BCR) signal pathways after antigen engagement, including the PI3K, MAPK, and NF-κB pathways (Figure 1), regulating the survival, activation, proliferation, and differentiation to antibody-producing plasma cells [9,10]. Additionally, BTK plays a critical role signaling through FcRγ-associated receptor in myeloid cells (macrophages and microglial cells), and has high affinity for IgE receptor in mast cells, leading to the secretion of pro-inflammatory cytokines as well as degranulation and histamine release. Moreover, BTK is a non-canonical pathway that is activated downstream of different Toll-like receptors (TLRs [11,12]). Therefore, inhibiting BTK could block the activation of different down-stream cell signaling pathways related to the development of B cell malignancies, and autoimmune diseases. BTK inhibitors can be classified into two types based on their mode of binding to BTK: i) Irreversible inhibitors form a covalent bond with the amino acid residue Cys481 in the ATP binding site of BTK, exerting a powerfully effective clinical benefit; ii) Reversible inhibitors, bind to specific pockets in the targets by weak, reversible forces (hydrogen bonds or hydrophobic interactions), determining an inactive conformation of the kinase. They can be easily removed, and as a result, they lack inhibitory potency and selectivity. Most of the molecules being active in the current clinical trials belong to irreversible BTK inhibitors [13].
Figure 1. BTK signal transduction pathways. After BCR is activated by phosphorylation, it recruits spleen tyrosine kinase (SYK) to the membrane where it is phosphorylated and subsequently phosphorylates Bruton’s tyrosine kinase (BTK). Phosphorylated BTK is recruited to the plasma membrane via autophosphorylation of Tyr223 in the SRC homology domain, and phosphorylates PLCγ2. Activated PLCγ2 hydrolyzes phosphatidyl inositol 4,5-biphosphate (PIP2), which results in the generation of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 upregulates calcium levels and DAG mediates activation of protein kinase Cβ (PKCβ). Increased of calcium levels, activation of PLCγ2, and PKCβ in turn promote the activation of the NF-κB-, ERK-, and NFAT-dependent pathways, which control the transcriptional expression of genes involved in proliferation, survival and cytokines secretion. In order to facilitate the understanding of the figure, some intermediate pathways have not been drawn. Ag: antigen; BCAP: B cell adaptor for PI3K; BCR: B cell receptor; BLNK: B cell linker; BTK: Bruton’s tyrosine kinase; DAG: diacylglycerol; ERK: extracellular-signal-regulated kinase; Igα/Igβ: signal transduction moiety (CD79); IKK: IκB kinase; IP3: inositol 1,4,5-triphosphate; NFAT: nuclear factor of activated T cells; NF-κB: nuclear factor κB; PKCβ: protein kinase Cβ; PLCγ2: phospholipase C-γ2. SYK: spleen tyrosine kina
The small molecule irreversible BTK inhibitor, ibrutinib is approved for the treatment of B cell malignancies, as well as graft versus host disease. However, ibrutinib inhibits a large number of kinases other than BTK, and the substantial off-target activity of the molecule preclude its evaluation in autoimmune diseases. To improve the overall tolerability of BTK inhibitors while maintaining the efficacy of ibrutinib, new BTK inhibitors have been developed [14].
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