Smac/DIABLO (second mitochondria-derived activator of caspases, or direct IAP binding protein with low pI) is a potent pro-apoptotic protein released from mitochondria in response to apoptotic stimuli. Recent studies have demonstrated that small-molecule Smac mimetics may have great therapeutic potential as a new class of anti-cancer agents to overcome apoptosis-resistance of cancer cells to current therapeutic agents by directly targeting inhibitor of apoptosis (IAP) proteins. We have designed and synthesized potent, conformationally constrained, non-peptide, Smac mimetic. We determined that these Smac mimetics bind to XIAP and other IAP proteins with low nanomolar affinities and overcome the anti-apoptotic activity of XIAP in model cells. Furthermore, these potent Smac mimetics are effective in enhancing the anti-tumor activity of chemotherapeutic agents and TRAIL in vitro and in vivo. Together, our data strongly demonstrate that potent, drug-like, non-peptide small-molecule Smac mimetics may be developed as a new class of highly promising therapeutic agents for the treatment of human cancer by directly targeting IAP proteins and overcoming apoptosis resistance of cancer cells.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]