Abstract
CLL cells express relatively high-levels of XIAP, a principle downstream inhibitor of procaspase activation that also is expressed in many other types of cancer. Expression of XIAP may contribute to the resistance of CLL cells (and other cancers in general) to apoptosis induced by anti-cancer drugs and immune effector mechanisms. The anti-apoptotic activity of XIAP can be circumvented by SMAC, a natural inhibitor to the inhibitors of apoptosis (IAPs) that is released from mitochondria following activation of the intrinsic apoptotic pathway. SMAC inhibits XIAP by blocking its BIR domain(s), thereby precluding XIAP from inhibiting active caspases, such as caspase 9. Using mixture-based combinatorial libraries, we identified a series of polyphenylureas that selectively target the BIR2 domain of XIAP and that do not compete with SMAC for binding to XIAP (
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