Send to

Choose Destination
J Med Chem. 2014 Mar 27;57(6):2726-35. doi: 10.1021/jm500045x. Epub 2014 Feb 25.

Structurally novel highly potent proteasome inhibitors created by the structure-based hybridization of nonpeptidic belactosin derivatives and peptide boronates.

Author information

Faculty of Pharmaceutical Sciences and ‡Center for Research and Education on Drug Discovery, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.


We previously developed highly potent proteasome inhibitor 1 (IC50 = 5.7 nM) and its nonpeptide derivative 2 (IC50 = 29 nM) by systematic structure-activity relationship studies of the peptidic natural product belactosin A and 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-lactone warhead with a more stable boronic acid warhead. Importantly, belactosin derivatives bind mainly to the proteasome binding site, which is different from that occupied by known peptide boronate proteasome inhibitors such as bortezomib, suggesting that their hybridization might lead to the development of novel potent inhibitors. Here we describe design, synthesis, and biological activities of the newly developed potent hybrid proteasome inhibitors. Interestingly, these hybrids, unlike bortezomib, were highly selective for proteasomes and have long residence times despite having the same boronic acid warhead.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center