CB988

CB988 is a highly selective, non-covalent, and reversible inhibitor of Bruton's tyrosine kinase (Btk), developed by Carna Biosciences. It was specifically designed to address the clinical challenge of ibrutinib resistance, which often arises from a C481S mutation in the Btk protein that disrupts the irreversible binding of covalent inhibitors. CB988 demonstrates sub-nanomolar potency against both the activated and unactivated forms of wild-type Btk, as well as the ibrutinib-resistant C481S mutant. Preclinical studies indicate that CB988 effectively reduces Btk autophosphorylation and downstream signaling through PLC-γ in B-cell lymphoma cell lines, and significantly inhibits the proliferation of ABC-type diffuse large B-cell lymphoma (DLBCL) cells. Its reversible binding mechanism and activity against the C481S mutant suggest potential therapeutic utility in patients with B-cell malignancies who have relapsed or are refractory to ibrutinib therapy.