Apoptosis has recently become one of the most intriguing fields explored in cancer therapy. Members of the inhibitor of apoptosis protein family (IAP) are overexpressed in many cancers. IAPs bind the caspase family of apoptotic enzymes, inhibiting their catalytic activity and preventing the programmed cell death. In particular the BIR3 domain of XIAP (human X linked IAP) blocks the active subunit of caspase-9, an initiator caspase of the mitochondria apoptosis pathway. In apoptotic cells the protein Smac/DIABLO has been demonstrated to compete with caspase-9 in binding XIAP through four N-terminal residues Ala-Val-Pro-Ile.

A set of XIAP inhibitors has been designed and synthesized in order to mimic Smac interaction with the BIR3 domain of XIAP.

Multi Component Reaction Chemistry (MCR) was adopted as synthetic strategy: diversified reaction products were obtained starting from the combination of three or four building blocks in a one pot operation. Based on the binding fragment Ala-Val novel potent scaffolds have been discovered also showing cell based activity.

X-ray studies of the synthesized inhibitors with the XIAP binding site compared to the Smac-XIAP complex showed that the H bounds of the Ala-Val portion are retained and can therefore contribute to the selectivity for the target. Instead, the high variability of the heterocyclic moiety leads to new additive interactions with XIAP.

Biological evaluations performed showed promising results, suggesting that a further expansion of the chemical diversity of the heterocyclic moiety may increase the interaction with XIAP.