BCL-XL PROTAC

BCL-XL PROTAC (B-cell lymphoma extra-large proteolysis-targeting chimera) represents a class of targeted protein degraders designed to selectively eliminate the anti-apoptotic protein BCL-XL (encoded by the *BCL2L1* gene) via the ubiquitin-proteasome system. Developed primarily by researchers at the University of Florida, the University of Texas Health Science Center at San Antonio, and licensed to Dialectic Therapeutics, these degraders (such as the clinical-stage candidate DT2216) utilize a BCL-XL-binding warhead (often derived from navitoclax) conjugated to an E3 ligase ligand (such as VHL or CRBN). By recruiting E3 ligases that are poorly expressed in platelets but highly expressed in cancer cells, BCL-XL PROTACs achieve tumor-selective BCL-XL degradation while sparing platelets from the dose-limiting thrombocytopenia associated with conventional BCL-XL small-molecule inhibitors. This platform is being investigated for the treatment of various BCL-XL-dependent malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), small-cell lung cancer (SCLC), and solid tumors, as well as for its potential senolytic and immunomodulatory effects (such as depleting tumor-induced regulatory T cells).

Other names

BCL-XL degraderBCL-XL proteolysis-targeting chimeraBCL-XL-targeting PROTACBcl-xL PROTAC