title: α-Keto phenylamides as P1'-extended proteasome inhibitors.
abstract: The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off-target-related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA-approved proteasome inhibitors bortezomib (1) or carfilzomib (2). A systematic comparison of electrophilic headgroups recently identified the class of α-keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure-activity relationship (SAR)-based approach for rational ligand design using an electronic parameter (Hammett's σ) and in silico molecular modeling. This resulted in the tripeptidic α-keto phenylamide BSc4999 [(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimethylphenyl)hexanamide, 6 a], a highly potent (IC50 = 38 nM), cell-permeable, and slowly reversible covalent inhibitor which targets both the primed and non-primed sites of the proteasome's substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α-keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.
authors.affiliation: Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany).
authors.forename: Constantin
authors.initials: C
authors.lastname: Voss
authors.forename: Christoph
authors.initials: C
authors.lastname: Scholz
authors.forename: Sabine
authors.initials: S
authors.lastname: Knorr
authors.forename: Philipp
authors.initials: P
authors.lastname: Beck
authors.forename: Martin L
authors.initials: ML
authors.lastname: Stein
authors.forename: Andrea
authors.initials: A
authors.lastname: Zall
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Kay
authors.initials: K
authors.lastname: Hamacher
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: 20S proteasome; Passerini reaction; cancer; drug development; ubiquitin