Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity.
Perez HL, Chaudhry C, Emanuel SL, Fanslau C, Fargnoli J, Gan J, Kim KS, Lei M, Naglich JG, Traeger SC, Vuppugalla R, Wei DD, Vite GD, Talbott RL, Borzilleri RM.
The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.