Antagonism of c-IAP and XIAP Proteins Is Required for Efficient Induction of Cell Death by Small-Molecule IAP Antagonists

• DOI: 10.1021/cb900083m
• Publication Date: 2009-06-03T19:10:27Z
• Authors: Chudi Ndubaku; Eugene Varfolomeev; Lan Wang; Kerry Zobel; Kevin Lau; Linda O. Elliott; Brigitte Maurer; Anna V. Fedorova; Jasmin N. Dynek; Michael Koehler; Sarah G. Hymowitz; Vickie Tsui; Kurt Deshayes; Wayne J. Fairbrother; John A. Flygare; Domagoj Vucic
• Keywords: XIAP; Inhibitor of apoptosis; Clonogenic assay

The inhibitor of apoptosis (IAP) proteins are critical regulators cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design IAP antagonists with high affinities and selectivity (>2000-fold) c-IAP1 over XIAP their functional characterization as activators tumor cells. Although capable inducing death preventing clonogenic c-IAP-selective significantly less potent promoting when compared to pan-selective compounds. However, both pan-IAP- stimulate c-IAP2 degradation activation NF-kappaB pathways comparable potencies. Therefore, although compounds that specifically target apoptosis, antagonism c-IAP is required efficient induction by antagonists.