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  • Title: Urea-containing peptide boronic acids as potent proteasome inhibitors.
    Author: Han LQ, Yuan X, Wu XY, Li RD, Xu B, Cheng Q, Liu ZM, Zhou TY, An HY, Wang X, Cheng TM, Ge ZM, Cui JR, Li RT.
    Journal: Eur J Med Chem; 2017 Jan 05; 125():925-939. PubMed ID: 27769033.
    Abstract:
    A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC50 < 1 pM), similar potency against four different cancer cell lines (IC50 < 10 nM), and better pharmacokinetic profile. Furthermore, I-14 significantly inhibited tumor growth in Bel7404 mouse xenograft model. The excellent proteasome inhibition by I-14 was rationalized through docking and molecular dynamics studies.
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