Bruton's tyrosine kinase C481S mutant (BTK C481S)

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec family that plays a pivotal role in the B-cell receptor (BCR) signaling pathway, which is essential for the development, proliferation, and survival of B-cells. The C481S mutation involves a substitution of cysteine with serine at position 481 in the ATP-binding pocket, which is the critical binding site for first-generation (ibrutinib) and second-generation (acalabrutinib, zanubrutinib) covalent BTK inhibitors. This mutation disrupts the formation of the covalent bond required for irreversible inhibition, leading to clinical resistance and disease progression in patients with B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). To address this, non-covalent BTK inhibitors like pirtobrutinib have been developed to bind reversibly to the kinase regardless of the C481 status, effectively restoring pathway inhibition. Additionally, novel therapeutic strategies such as BTK degraders (PROTACs) are being investigated to overcome resistance by inducing the ubiquitination and proteasomal degradation of the mutant protein.

Other names

BTK C481SBruton agammaglobulinemia tyrosine kinase C481SC481S-mutated BTKTyrosine-protein kinase BTK C481S mutant

Non-covalent (reversible) inhibition of the ATP-binding site and targeted protein degradation via E3 ubiquitin ligase recruitment