Inhibitors of apoptosis proteins (IAPs) are considered as promising new cancer therapeutic targets and Smac protein is the natural antagonist of IAP proteins. Small-molecule Smac mimetics have been designed and developed as antagonists of IAP proteins. SM-406 is a potent and orally bioavailable small-molecule Smac mimetic designed in our laboratory and is in Phase I clinical development for cancer treatment. Based upon SM-406, a series of new and non-peptidic Smac mimetics were designed, synthesized and evaluated. A number of these new Smac mimetics potently bind to XIAP, cIAP-1 and cIAP-2, efficiently inhibit cell growth and induce robust apoptosis in a subset of cancer cell lines at low nanomolar concentration. The most promising compounds also show improved pharmacokinetic properties over SM-406/AT-406 and effectively inhibit tumor growth in the MDA-MB-231 xenograft model.

Orally bioavailable Smac mimetics as antagonists of IAP proteins

243rd National Meeting (2012)

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