Bruton protein-tyrosine kinase (BTK) FDA-approved small molecule inhibitors used for the management of neoplastic and inflammatory disorders

The Bruton nonreceptor protein-tyrosine kinase (BTK) plays a central role in B cell antigen receptor signaling. Following B cell receptor activation, the Src protein kinase Lyn and the spleen protein kinase (Syk) activate BTK. It then mediates the phosphorylation and activation of phospholipase Cγ2 (PLCγ2). The Ras/RAF/MEK/ERK and NF-κB pathways are downstream of PLCγ2. These signaling modules participate in the affinity maturation of antibody-producing B cells by somatic hypermutation. The absence of BTK results in X-linked agammaglobulinemia. BTK contains an amino-terminal PH (pleckstrin homology) domain that interacts with phosphatidyl inositol trisphosphate within the plasma membrane to promote its membrane association. This is followed by a TEC homology segment, an SH3 and SH2 domain, and finally a carboxyterminal protein kinase domain. Aberrant B cell receptor signaling occurs in several B cell neoplasms including follicular lymphoma (treated with zanubrutinib, a BTK inhibitor), mantle cell lymphoma (acalabrutinib, pirtobrutinib, zanubrutinib), marginal zone lymphoma (zanubrutinib), chronic lymphocytic leukemia and small lymphocytic lymphoma (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), and Waldenström macroglobulinemia (ibrutinib, zanubrutinib). Chronic spontaneous urticaria and chronic immune thrombocytopenia are driven by B cell dysfunction. The former is treated with remibrutinib and the latter is treated with rilzabrutinib, both of which inhibit BTK. Four drugs (ibrutinib, acalabrutinib, zanubrutinib, remibrutinib) form an irreversible covalent bond and rilzabrutinib forms a reversible covalent bond with BTK Cys481. Pirtobrutinib fails to form a covalent bond and is a reversible BTK inhibitor. The FDA-approvals of rilzabrutinib and remibrutinib (2025) represent the first nononcologic authorizations for BTK antagonists.