Development of peptide epoxyketones as selective immunoproteasome inhibitors.
A series of epoxyketone analogues with varying N-caps and P3-configurations were designed, synthesized and evaluated. We found that D-Ala in P3 was crucial for β5i selectivity over β5c. Notably, compounds 20j (β5i IC50 = 26.0 nM, 25-fold selectivity) and 20l (β5i IC50 = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of β5i alone is not sufficient to exert anticancer effects and may rely on the complementary inhibition of β1i, β5c and β5i. These data further increase our understanding of immunoproteasome inhibitors in hematologic malignancies.
['Li|Xuemei|X|', 'Hong|Duidui|D|', 'Zhang|Mengmeng|M|', 'Xu|Lei|L|', 'Zhou|Yubo|Y|', 'Li|Jia|J|', 'Liu|Tao|T|']
D000970:Antineoplastic Agents D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D000076722:Drug Development D004354:Drug Screening Assays, Antitumor D004852:Epoxy Compounds D006801:Humans D007659:Ketones D062105:Molecular Docking Simulation D015394:Molecular Structure D010455:Peptides D046988:Proteasome Endopeptidase Complex D061988:Proteasome Inhibitors D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
Epoxyketones Selectivity Immunoproteasome inhibitor Multiple myeloma