Abstract
Abstract Evasion of cell death is a characteristic feature of human cancers and represents a key cause of resistance to current treatment approaches. Therefore, reactivation of cell death programs in cancer cells is a promising strategy to overcome treatment resistance, one of the major unsolved problems in clinical oncology. Inhibitor of apoptosis (IAP) protein family members block cell death in response to diverse stimuli and are expressed at elevated levels in the majority of human malignancies, which makes them attractive targets for developing a novel class of cancer therapeutics. We have designed small-molecule IAP antagonists (smac mimetics) that bind with high affinities to select baculovirus IAP repeat (BIR) domains of IAPs resulting in a dramatic induction of c IAP auto-ubiquitination activity and rapid proteasomal degradation. IAP antagonists inhibit tumor growth in vivo as single agents and in combination with a number of anti-tumor agents. Using several different proteomic approaches we have discovered novel binding partners for IAP proteins and determined the spatial and temporal pattern of endogenous IAP-mediated ubiquitination during proliferative, apoptotic and necrotic signaling. The differential expression levels and posttranslational modifications of identified proteins will be used to build diagnostic profiles for the treatment with IAP antagonists. These compounds can be used in the treatment of malignancies in which IAP expression contributes to tumor progression and resistance to conventional chemotherapeutic agents. Citation Format: Domagoj Vucic. Targeting IAP proteins for the treatment of cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY06-01. doi:10.1158/1538-7445.AM2013-SY06-01
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