Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-derived Activator of Caspases

A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized and evaluated. The most potent compound (6) binds to XIAP, cIAP-1 and cIAP-2 with Ki values of 8.4, 1.5 and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line and has a good oral bioavailability.