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
  • 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: [email protected].
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: [email protected].
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.