A-155463

A-155463 is a highly potent and selective small molecule inhibitor of B-cell lymphoma-extra large (BCL-XL), a member of the BCL-2 family of proteins that regulates the intrinsic apoptotic pathway. Developed by AbbVie, A-155463 was designed as a tool compound to specifically interrogate BCL-XL biology without the concomitant BCL-2 inhibition associated with dual inhibitors like navitoclax. It functions as a BH3-mimetic, binding with high affinity to the BH3-binding groove of BCL-XL and preventing it from sequestering pro-apoptotic proteins such as BAK and BAX. This neutralization triggers programmed cell death in cells that are dependent on BCL-XL for survival. While primarily utilized as a research reagent to study BCL-XL dependency in various cancers and its role in cellular senescence (senolysis), A-155463 has also served as the structural basis for the development of BCL-XL-targeting antibody-drug conjugates (ADCs) and PROTACs intended for clinical use.