Smac mimetics as new cancer therapeutics.

ABSTRACT

The recent discovery of Smac and the elucidation of its structure and function have led to the rapid development of Smac mimetics, comprising Smac derivative and mimicking molecules, for use in cancer treatment. Smac is an endogenous proapoptotic protein that resides in the mitochondria and is released when a cell is triggered to undergo programmed cell death. One of the mechanisms by which Smac promotes apoptosis is through its ability to inhibit inhibitors of apoptosis (IAPs), by direct inhibition and/or proteasomal degradation of some members of the IAP family, and therefore disinhibit caspases. Thus, the use of Smac mimetics as anticancer agents follows a rational approach in cancer therapeutics. This approach directly targets dysregulated, neoplastic cells that overexpress IAPs or underexpress Smac. Although Smac mimetics are able to elicit an anticancer response when used alone, these molecules can also function effectively and synergistically when combined with other therapeutic agents. A variety of Smac mimetic types comprising peptides, polynucleotides, and compounds have been studied both in vitro and in vivo. This discussion addresses the current status of Smac mimetics in cancer research.