Design of small-molecule Smac mimetics as IAP antagonists.

Smac/DIABLO, discovered in 2000 as a protein released from mitochondria into the cytosol in response to apoptotic stimuli, functions as an endogenous antagonist of X-linked inhibitor of apoptosis protein (XIAP) and several other IAP proteins through direct binding. The interaction between Smac and IAPs involves the AVPI tetrapeptide binding motif on the N-terminus of Smac and a well-defined groove on the surface of these IAP proteins, providing an ideal site for the design of small-molecule Smac mimetics. Potent and cell-permeable small-molecule Smac mimetics have provided powerful pharmacological tools for study of the regulation of apoptosis by IAP proteins, and several such compounds are now in early clinical trials as new anticancer agents.