The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.
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2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models