Bruton's tyrosine kinase (BTK) (BTK)

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the Tec family, primarily expressed in B-cells and myeloid cells [6, 8]. It serves as a critical mediator in the B-cell receptor (BCR) signaling pathway, which is essential for B-cell development, activation, and survival [2, 13]. Upon BCR engagement, BTK is activated and subsequently phosphorylates downstream targets like PLCγ2, leading to calcium mobilization and activation of transcription factors such as NF-κB [6, 16]. Dysregulation or overactivation of BTK is a hallmark of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), making it a primary therapeutic target [7, 20]. Pirtobrutinib is a next-generation, highly selective, non-covalent BTK inhibitor designed to overcome resistance encountered with earlier covalent inhibitors, such as those caused by the C481S mutation [1, 3]. By binding to the ATP-binding site without requiring a covalent bond, pirtobrutinib effectively inhibits both wild-type and mutant BTK, providing a vital treatment option for patients with relapsed or refractory disease [4, 19].

Other names

Agammaglobulinemia tyrosine kinaseATKB-cell progenitor kinaseBPKIMD1PSCTK1Tyrosine-protein kinase BTK

Pirtobrutinib is a highly selective, non-covalent (reversible) inhibitor of Bruton's tyrosine kinase (BTK). It binds to the ATP-binding pocket of the enzyme, stabilizing it in a closed, inactive conformation and preventing the phosphorylation of the activation loop at residue Y551 [1, 3]. This action blocks the B-cell receptor (BCR) signaling pathway, inhibiting downstream activation of PLCγ2, AKT, and NF-κB, which leads to the induction of apoptosis and inhibition of proliferation in malignant B-cells [2, 16]. Unlike covalent inhibitors, pirtobrutinib does not require binding to the C481 residue, allowing it to remain effective against BTK variants with C481 mutations [4, 20].