摘要：

SY07-04Inhibition of apoptosis enhances the survival of cancer cells and facilitates their escape from immune surveillance and cytotoxic therapies. Inhibitor of apoptosis (IAP) protein family members are anti-apoptotic regulators that block cell death in response to diverse stimuli. IAP proteins are expressed at elevated levels in the majority of human malignancies and because they play an active role in promoting tumor maintenance they are attractive targets for developing a novel class of cancer therapeutics. We demonstrate that both monovalent and bivalent small-molecule IAP antagonists bind with high affinities to select baculovirus IAP repeat (BIR) domains of XIAP or c-IAPs and disrupt critical IAP:caspase and IAP:SMAC interactions in a dose dependent manner. Binding of IAP antagonists results in dramatic induction of c IAP auto-ubiquitination activity and rapid proteasomal degradation. Besides neutralizing these anti-apoptotic proteins, the IAP antagonists actively induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. The c-IAP1 and c-IAP2 proteins were also found to function as regulators of NF-κB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the non-canonical NF-κB pathway. Finally, our IAP antagonists inhibit tumor growth in vivo as single agents and in combination with a number of standard of care anti-tumor agents. Understanding the significance of protein stability and caspase/SMAC interactions for inhibition of apoptosis by IAP proteins is important for the design of potent IAP-directed compounds for treatment of melanomas and other malignancies in which IAP expression contributes to tumor progression and resistance to conventional chemotherapeutic agents.

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