2. Academic Validation
  3. Urea-containing peptide boronic acids as potent proteasome inhibitors

Urea-containing peptide boronic acids as potent proteasome inhibitors

  • Eur J Med Chem. 2017 Jan 5:125:925-939. doi: 10.1016/j.ejmech.2016.10.023.
Li-Qiang Han 1,  Xia Yuan 1,  Xing-Yu Wu 1,  Ri-Dong Li 1,  Bo Xu 1,  Qing Cheng 1,  Zhen-Ming Liu 1,  Tian-Yan Zhou 1,  Hao-Yun An 2,  Xin Wang 1,  Tie-Ming Cheng 1,  Ze-Mei Ge 3,  Jing-Rong Cui 4,  Run-Tao Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
  • 2 Zhengzhou Granlen PharmaTech, Ltd., 1300 East Hanghai Road, Zhengzhou, Henan 450016, PR China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: zmge@bjmu.edu.cn.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: jrcui@bjmu.edu.cn.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: lirt@bjmu.edu.cn.
PMID: 27769033 DOI: 10.1016/j.ejmech.2016.10.023
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.

Keywords

Anti-tumor activity; Low toxicity; Proteasome inhibitor; Structure-activity relationship; Urea-containing peptide boronic acids.

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