# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 2 Bruton Tyrosine Kinase
#### Bruton Tyrosine Kinase's Inhibitors  
BTKis represent a promising class of small molecules capable of selectively modulating immune signaling pathways implicated in both peripheral and central inflammation (Figure 1) [29; 30]. Initially developed for B-cell malignancies, BTKis are now being investigated for their potential to attenuate neuroinflammatory, a pathological hallmark shared across multiple neurodegenerative disorders [31]. These inhibitors can be categorized by their mechanism of binding (Figure 2), which can be irreversible (covalent) or reversible (non-covalent), and have evolved through successive generations to optimize selectivity, pharmacokinetics, and CNS accessibility, broadening their applicability beyond hematologic malignancies to autoimmune and neurodegenerative conditions [32]. First-generation BTKis, such as ibrutinib, irreversibly bind to the conserved cysteine residue (Cys481) within BTK's ATP-binding pocket via covalent Michael addition, displaying potent inhibition but limited selectivity due to off-target binding to other kinases. Indeed, although effective with modest BBB penetration, ibrutinib exhibits off-target binding to kinases like tyrosine-protein kinase (TEC), epidermal growth factor receptor (EGFR),  
Figure 1: Overview of BTK’s signaling and inhibition mechanisms. Figure 2: Overview of BTK inhibitors’ binding mechanisms. and interleukin-2-inducible T-cell kinase (ITK), leading to a broad side-effect profile that includes atrial fibrillation, hypertension, diarrhea, and bleeding due to impaired platelet aggregation [29; 33]. Second-generation inhibitors, including acalabrutinib and zanubrutinib, retain irreversible covalent binding to Cys481 but were designed for enhanced selectivity and reduced off-target toxicity. Acalabrutinib, for instance, does not inhibit Src-family kinases, a major advancement over birutinib in terms of platelet safety. Zanubrutinib similarly demonstrates minimal inhibition of ITK and is associated with lower incidence of cardiac events, which positions it as a safer alternative in B-cell malignancies such as mantle cell lymphoma and chronic lymphocytic leukemia. Both compounds maintain high BTK occupancy and plasma stability, allowing effective B-cell inhibition with a better side-effect profile. However, their limited CNS penetration curtails their utility in neuroinflammatory disorders [34; 35]. Third-generation BTKis include reversible and hybrid covalent-reversible inhibitors such as rilzabrutinib and fenebrutinib [36; 37]. These agents bind either non-covalently or via transient covalent bonds to BTK, thus offering the potential to overcome resistance mutations such as C481S, which limit the efficacy of irreversible BTKis. Reversible inhibitors like fenebrutinib interact with alternative residues in the SH3 domain (e.g., K430, M477), avoiding reliance on Cys481 for activity and providing utility in autoimmune indications such as MS [38]. Rilzabrutinib, a hybrid inhibitor, demonstrates high target occupancy in vivo and favorable pharmacokinetics with minimal systemic exposure, suggesting potential for chronic use with reduced toxicity [36]. The other third-generation inhibitors are orelabrutiinib and remibrutinib, able to further enhance specificity and bioavailability, with minimal inhibition of kinases unrelated to BTK and promising CNS exposure [39; 40]. The adverse effects vary by generation: first-generation compounds are associated with systemic immunosuppression and cardiovascular events, whereas newer agents show reduced systemic toxicity [34]. CNS-penetrant BTKis, such as tolebrutinib and evobrutinib, have emerged as leading candidates for the treatment of neurodegenerative disorders. These compounds possess optimized physicochemical properties, allowing efficient BBB crossing and central BTK engagement [41]. Tolebrutinib, for instance, achieves therapeutic concentrations in CNS tissue and modulates microglial responses without broadly suppressing systemic immunity [42].