Publications (2)8.97 Total impact
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Article: Targeting inhibitor of apoptosis proteins for therapeutic intervention.
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ABSTRACT: The inhibitors of apoptosis (IAP) proteins have emerged over the last decade as important targets for therapeutic intervention in human malignancies. Overexpression of IAPs has been implicated in cell survival and resistance against stress-induced apoptosis brought on by radiation and/or chemotherapeutics (currently the standard-of-care in a variety of different cancer diseases). In addition, evasion from death receptor-mediated apoptosis and regulation of NF-κB pathways and cell division have also been associated with IAP proteins. Efforts to target IAP proteins in tumors have focused mainly on designing small molecules that mimic the IAP-binding motif of the endogenous IAP antagonist, second mitochondrial activator of caspases. In addition, several other IAP-targeting strategies, including antisense oligonucleotides and transcriptional repression, have also been initiated, with the hope of providing therapeutic benefit to cancer patients.Future medicinal chemistry 11/2009; 1(8):1509-25. · 2.52 Impact Factor -
Article: Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.
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ABSTRACT: The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their functional characterization as activators of apoptosis in tumor cells. Although capable of inducing cell death and preventing clonogenic survival, c-IAP-selective antagonists are significantly less potent in promoting apoptosis when compared to pan-selective compounds. However, both pan-IAP- and c-IAP-selective antagonists stimulate c-IAP1 and c-IAP2 degradation and activation of NF-kappaB pathways with comparable potencies. Therefore, although compounds that specifically target c-IAP1 and c-IAP2 are capable of inducing apoptosis, antagonism of the c-IAP proteins and XIAP is required for efficient induction of cancer cell death by IAP antagonists.ACS Chemical Biology 06/2009; 4(7):557-66. · 6.45 Impact Factor
