title: Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones.
abstract: Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure-activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable β-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient α,β-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawamura
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka 422-8526, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Unno
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka 422-8526, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: shu@pharm.hokudai.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D036341:Intercellular Signaling Peptides and Proteins; D007659:Ketones; D010446:Peptide Fragments; D010455:Peptides; D061988:Proteasome Inhibitors; C406052:belactosin A; D046988:Proteasome Endopeptidase Complex
keywords: Belactosin A; Epoxyketone; Proteasome inhibitor