2. Academic Validation
  3. Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides

Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides

  • Bioorg Chem. 2025 Mar:156:108180. doi: 10.1016/j.bioorg.2025.108180.
Gongruixue Zeng 1,  Gaoya Xu 2,  Lixin Gao 3,  Xiaoli Zheng 4,  Xinglong Chi 5,  Zheyuan Shen 6,  Yu Cao 7,  Jianjun Xi 7,  Jinxin Che 6,  Xiaowu Dong 6,  Yaoli Shi 4,  Jiayi Ma 4,  Chong Zhang 1,  Linghui Zeng 1,  Huajian Zhu 1,  Jiaan Shao 1,  Yubo Zhou 8,  Jia Li 9,  Jiankang Zhang 10
Affiliations

Affiliations

  • 1 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang Province, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University China.
  • 5 Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang Province, China.
  • 7 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023 Zhejiang Province, China.
  • 8 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 9 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
  • 10 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 Zhejiang Province, China. Electronic address: zhang_jk@hzcu.edu.cn.
PMID: 39855110 DOI: 10.1016/j.bioorg.2025.108180
Abstract

Cyclization is a pivotal strategy for enhancing the drug-like characteristics of polypeptides. To develop potent and metabolically stable Proteasome inhibitors, we generated a macrocyclic peptide skeleton using a straightforward and efficient cyclization strategy. Subsequent stability assessments confirmed the practicality of this approach. Leveraging this skeleton, we designed and synthesized a series of epoxyketone macrocyclic peptidyl Proteasome inhibitors. Approximately half of these compounds showcased robust inhibitory potency, with IC50 values below 200 nM against chymotrypsin-like (ChT-L, β5) activity. Notably, compounds 6f, 6g, and 6m demonstrated pronounced anti-proliferative activities at low nanomolar concentrations against three hematoma cell lines (RPMI-8226, RS4;11, and MV-4-11) as well as the NCI-H1299 cell line. These findings highlight the potential of these cyclic Peptides to bolster the stability of Proteasome inhibitors, thereby providing valuable insights for the advancement of innovative Proteasome Inhibitor therapies.

Keywords

Anti-cancer activities; Macrocycle; Proteasome inhibitors; Stability.

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