Structurally Novel HighlyPotent Proteasome InhibitorsCreated by the Structure-Based Hybridization of Nonpeptidic BelactosinDerivatives and Peptide Boronates.

Wepreviously developed highly potent proteasome inhibitor 1(IC50= 5.7 nM) and its nonpeptide derivative 2(IC50= 29 nM) by systematic structure–activityrelationship studies of the peptidic natural product belactosin Aand subsequent rational topology-based scaffold hopping, respectively.Their cell growth inhibitory activities, however, were only moderate(IC50= 1.8 μM (1) and >10 μM(2)). We therefore planned to replace the unstable β-lactonewarhead with a more stable boronic acid warhead. Importantly, belactosinderivatives bind mainly to the proteasome binding site, which is differentfrom that occupied by known peptide boronate proteasome inhibitorssuch as bortezomib, suggesting that their hybridization might leadto the development of novel potent inhibitors. Here we describe design,synthesis, and biological activities of the newly developed potenthybrid proteasome inhibitors. Interestingly, these hybrids, unlikebortezomib, were highly selective for proteasomes and have long residencetimes despite having the same boronic acid warhead. [ABSTRACT FROM AUTHOR]