Definition

An orally bioavailable inhibitor of Bruton’s tyrosine kinase (BTK; Bruton agammaglobulinemia tyrosine kinase), with potential antineoplastic activity. Upon oral administration, BTK inhibitor LP-168 covalently binds to and inhibits the activity of wild-type (WT) BTK and non-covalently binds to inhibits the activity of C481 mutated BTK, a resistance mutation in the BTK active site in which cysteine is substituted for serine at residue 481 (C481S). 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. 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. BTK C481S mutation plays an important role in resistance to certain BTK inhibitors. This dual activity allows efficacy against tumor cells expressing WT BTK through covalent binding while simultaneously preventing the proliferation of tumor cells expressing the most common resistance mutation to covalent BTK inhibitors through non-covalent binding.