WEHI-539

WEHI-539 is a potent and highly selective small-molecule inhibitor of B-cell lymphoma-extra large (BCL-XL), an anti-apoptotic member of the BCL-2 protein family. Developed by researchers at the Walter and Eliza Hall Institute (WEHI), it was the first compound to demonstrate high affinity and selectivity for BCL-XL over other family members like BCL-2 and BCL-W. WEHI-539 functions by binding to the BH3-binding groove of BCL-XL, thereby preventing it from inhibiting pro-apoptotic proteins and triggering the intrinsic apoptotic pathway. While not progressed into clinical trials, WEHI-539 is an essential research tool used extensively in BH3 profiling to determine the apoptotic dependencies of various cancer cells, including multiple myeloma and leukemia, and to explore the therapeutic potential of targeting BCL-XL.