A series of hybrid compounds of bestatin (
1) and actinonin (
3), which promote degradation of cellular inhibitor of apoptosis protein 1 (cIAP1), were designed and synthesized. Structure–activity relationship studies indicated that absolute configuration, hydrophobicity at the
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-position of the internal amide carbonyl group, and the presence of a small substituent at the
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-position of the ester group are important factors for the expression of potent cIAP1 degradation-promoting activity. HAB-5A (
30b) showed the most potent activity (IC
50 = 0.53 μM) among the compounds prepared.