BTK

About BTK

BTK Bruton Tyrosine Kinase on chromosome Xq22.1 encodes a cytoplasmic tyrosine kinase essential for B cell receptor signaling and for B cell development in the bone marrow. Loss of function variants cause X linked agammaglobulinemia, in which affected boys have almost no mature B cells and very low levels of all classes of immunoglobulin. Symptoms typically begin in late infancy, after antibodies received from the mother wane, with recurrent bacterial infections such as otitis, sinusitis, pneumonia, and sepsis, and susceptibility to certain enteroviruses. The disease was described by Ogden Bruton in 1952, one of the first immunodeficiencies recognized, and the gene was identified in 1993. Treatment centers on lifelong immunoglobulin replacement given intravenously or subcutaneously. BTK is also a key therapeutic target in B cell cancers, whose growth depends on B cell receptor signaling. Covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib bind cysteine 481 in the kinase and are widely used for chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom macroglobulinemia. Resistance through the C481S mutation led to non covalent inhibitors such as pirtobrutinib. Ibrutinib is also approved for chronic graft versus host disease.