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Caspase\u20109 is an upstream or initiator caspase that is regulated differently from all other caspases, as interaction with natural inhibitor X\u2010linked inhibitor of apoptosis protein (XIAP)\u2010baculovirus inhibitory repeat 3 (BIR3) occurs at the dimer interface maintaining caspase\u20109 in an inactive monomeric state. One route to caspase\u20109\u2010specific inhibition is to mimic this interaction, which has been localized to the \u03b15 helix of XIAP\u2010BIR3. We have developed three types of stabilized peptides derived from the \u03b15 helix, using incorporation of aminoisobutyric acid, the avian pancreatic polypeptide (aPP)\u2010scaffold or aliphatic staples. The stabilized peptides are helical in solution and achieve up to 32 \u03bc<jats:italic>M<\/jats:italic> inhibition, indicating that this allosteric site at the caspase\u20109 dimerization interface is regulatable with low\u2010molecular weight synthetic ligands and is thus a druggable site. The most potent peptides against caspase\u20109 activity are the aPP\u2010scaffolded peptides. Other caspases, which are not regulated by dimerization, should not be inactivated by these peptides. Given that all of the peptides attain helical structures but cannot recapitulate the high\u2010affinity inhibition of the intact BIR3 domain, it has become clear that interactions of caspase\u20109 with the BIR3 exosite are essential for high\u2010affinity binding. These results explain why the full XIAP\u2010BIR3 domain is required for maximal inhibition and suggest a path forward for achieving allosteric inhibition at the dimerization interface using peptides or small molecules. \u00a9 2012 Wiley Periodicals, Inc. 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