Definition

A third-generation, reversible inhibitor of Bruton’s tyrosine kinase (BTK; Bruton agammaglobulinemia tyrosine kinase), with potential antineoplastic activity. Upon administration, BTK inhibitor HMPL-760 non-covalently binds to and inhibits the activity of both wild-type and the C481S mutated form of BTK, a resistance mutation in the BTK active site in which cysteine is substituted for serine at residue 481. This prevents the activation of the B-cell antigen receptor (BCR) signaling pathway and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B-cells that overexpress BTK or the C481S mutated form. BTK C481S mutation plays an important role in resistance to certain BTK inhibitors; HMPL-760 may be able to overome this resistance. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in the development, activation, signaling, proliferation and survival of B lymphocytes.