title: Urea-containing peptide boronic acids as potent proteasome inhibitors.
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.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Li-Qiang
authors: LQ
authors: Han
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Xia
authors: X
authors: Yuan
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Xing-Yu
authors: XY
authors: Wu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Ri-Dong
authors: RD
authors: Li
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Bo
authors: B
authors: Xu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Qing
authors: Q
authors: Cheng
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Zhen-Ming
authors: ZM
authors: Liu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Tian-Yan
authors: TY
authors: Zhou
authors: Zhengzhou Granlen PharmaTech, Ltd., 1300 East Hanghai Road, Zhengzhou, Henan 450016, PR China.
authors: Hao-Yun
authors: HY
authors: An
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Xin
authors: X
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors: Tie-Ming
authors: TM
authors: Cheng
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: zmge@bjmu.edu.cn.
authors: Ze-Mei
authors: ZM
authors: Ge
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: jrcui@bjmu.edu.cn.
authors: Jing-Rong
authors: JR
authors: Cui
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: lirt@bjmu.edu.cn.
authors: Run-Tao
authors: RT
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D014508:Urea / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D010455:Peptides; D061988:Proteasome Inhibitors; D014508:Urea; D046988:Proteasome Endopeptidase Complex
keywords: Anti-tumor activity; Low toxicity; Proteasome inhibitor; Structure-activity relationship; Urea-containing peptide boronic acids