Bruton tyrosine kinase (BTK) C481S mutant (BTK C481S)

Bruton tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec family that is critical for B-cell receptor (BCR) signaling, which regulates B-cell development, proliferation, and survival (NIH, 2025; Gu et al., 2021). The BTK C481S mutant is a clinically significant variant where the cysteine residue at position 481 is substituted with serine in the ATP-binding pocket (Woyach et al., 2014). This mutation is the most common mechanism of acquired resistance to covalent (irreversible) BTK inhibitors, such as ibrutinib, because it prevents the formation of the essential covalent bond between the drug and the enzyme (Mato et al., 2023; ResearchGate, 2015). As a result, patients with this mutation often experience disease progression in B-cell malignancies like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) (NIH, 2025). Non-covalent (reversible) BTK inhibitors, such as pirtobrutinib, have been specifically developed to target this mutant form by binding to the kinase domain through alternative interactions that do not depend on the C481 residue (Mato et al., 2023; Blood Advances, 2023). These agents provide a vital therapeutic option for overcoming resistance and maintaining suppression of the BCR signaling pathway in relapsed or refractory patients (NIH, 2025).

Other names

BTK(C481S)C481S-mutated Bruton tyrosine kinaseBTK C481S variantBruton's tyrosine kinase C481S

Reversible, non-covalent inhibition of the BTK kinase domain, bypassing the requirement for the Cys481 residue for binding (Mato et al., 2023; Gu et al., 2021).