Definition

An orally bioavailable chimeric degrader of Bruton’s tyrosine kinase (BTK) comprised of an E3 ubiquitin ligase ligand conjugated to a BTK-binding ligand, with potential antineoplastic activity. Upon oral administration, BTK degrader AC0676 specifically targets and binds to, with its BTK-targeting moiety, wild-type (WT) and various mutant forms, including, but not limited to, C481S and L528W. Upon binding, the E3 ubiquitin ligase ligand moiety binds to E3 ubiquitin ligase. This catalyzes ubiquitination and proteasome-mediated degradation of BTK, and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation 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 B-lymphocyte development, activation, signaling, proliferation and survival.