A-1155463

BCL-XL (B-cell lymphoma-extra large), also called BCL2L1, is a member of the BCL-2 family of proteins and is involved in regulating apoptosis. BCL-XL is part of the group of BCL-2 proteins considered pro-survival proteins, as when bound to their effector proteins they inhibit apoptosis.  BCL-XL plays a role in the permeability of mitochondrial membrane, allowing the release of cytochrome C. In addition to its role in apoptosis, it is also involved in neural growth, synaptic plasticity, and neuroprotection. As their name indicates, they are found at abnormal levels in B-cell lymphoma and may contribute to the progression of the disease. BCL-XL overexpression is found in about 80% of lymphomas, and it is thus an attractive target in cancer therapy. Recently it has been identified as being a player in autoimmune disorders and ageing, by controlling the apoptosis rate of immune cells, fibroblasts and other cell types. Several therapeutic approaches have been explored to target BCL-XL, ranging from small inhibitors, such as navitoclax, to PROTACs (proteolysis targeting chimeras) . PROTAC 753B, a PROTAC targeting BCL-XL/BCL2 to VHL (von Hippel-Lindau), has been shown to increase the effects of chemotherapy, while avoiding off-target effect on platelets, as these do not express VHL. Advances in small inhibitors are also ongoing and promise to bring benefit to oncologic patients.