title: Structurally novel highly potent proteasome inhibitors created by the structure-based hybridization of nonpeptidic belactosin derivatives and peptide boronates.
abstract: 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.
authors: 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.
authors: Shuhei
authors: S
authors: Kawamura
authors: Yuka
authors: Y
authors: Unno
authors: Akira
authors: A
authors: Asai
authors: Mitsuhiro
authors: M
authors: Arisawa
authors: Satoshi
authors: S
authors: Shuto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007783:Lactones / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013302:Streptomyces / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D036341:Intercellular Signaling Peptides and Proteins; D007783:Lactones; D010455:Peptides; D061988:Proteasome Inhibitors; C406052:belactosin A; D002403:Cathepsins