title: A Minimal β-Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors.
abstract: Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β-lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo-isoleucin) or an isopropyl (pseudo-valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC50=14 nM) than the valine counterpart. Cell culture experiments demonstrate the cell-permeability of the compounds and X-ray crystallography data highlight them as minimal fragments that occupy primed and non-primed pockets of the active sites of the proteasome. Together, these results qualify β-lactones as a promising lead-structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching (Germany). michael.groll@tum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching (Germany).
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Korotkov
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching (Germany).
authors.forename: Eva M
authors.initials: EM
authors.lastname: Huber
authors.affiliation: Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany).
authors.forename: Armin
authors.initials: A
authors.lastname: de Meijere
authors.affiliation: Charité Universitätsmedizin Berlin CCM, Medizinische Klinik für Kardiologie und Angiologie, Charitéplatz 1, 10117 Berlin (Germany). antje.ludwig@charite.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D001593:Benzyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001593:Benzyl Compounds; D007783:Lactones; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: cytotoxicity; immunoproteasome; inhibitors; lead structures; β-lactones