. 2021 Oct 5:221:113556.

doi: 10.1016/j.ejmech.2021.113556. Epub 2021 May 25.

Development of peptide epoxyketones as selective immunoproteasome inhibitors

Xuemei Li¹, Duidui Hong², Mengmeng Zhang³, Lei Xu⁴, Yubo Zhou⁵, Jia Li⁶, Tao Liu⁷

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
² Jiangsu Shengdia Industrial Co. Ltd., NO. 161 Shaoxing Road, Xiacheng District, Hangzhou, 310004, PR China.
³ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: ybzhou@simm.ac.cn.
⁶ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: jli@simm.ac.cn.
⁷ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China. Electronic address: Lt601@zju.edu.cn.

PMID: 34087498
DOI: 10.1016/j.ejmech.2021.113556

Development of peptide epoxyketones as selective immunoproteasome inhibitors

Xuemei Li et al. Eur J Med Chem. 2021.

. 2021 Oct 5:221:113556.

doi: 10.1016/j.ejmech.2021.113556. Epub 2021 May 25.

Authors

Xuemei Li¹, Duidui Hong², Mengmeng Zhang³, Lei Xu⁴, Yubo Zhou⁵, Jia Li⁶, Tao Liu⁷

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
² Jiangsu Shengdia Industrial Co. Ltd., NO. 161 Shaoxing Road, Xiacheng District, Hangzhou, 310004, PR China.
³ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: ybzhou@simm.ac.cn.
⁶ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: jli@simm.ac.cn.
⁷ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China. Electronic address: Lt601@zju.edu.cn.

PMID: 34087498
DOI: 10.1016/j.ejmech.2021.113556

Abstract

A series of epoxyketone analogues with varying N-caps and P3-configurations were designed, synthesized and evaluated. We found that D-Ala in P3 was crucial for β5i selectivity over β5c. Notably, compounds 20j (β5i IC₅₀ = 26.0 nM, 25-fold selectivity) and 20l (β5i IC₅₀ = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of β5i alone is not sufficient to exert anticancer effects and may rely on the complementary inhibition of β1i, β5c and β5i. These data further increase our understanding of immunoproteasome inhibitors in hematologic malignancies.

Keywords: Epoxyketones; Immunoproteasome inhibitor; Multiple myeloma; Selectivity.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Recent Advances in the Development of Immunoproteasome Inhibitors as Anti-Cancer Agents: The Past 5 Years.
Mancuso F, Di Chio C, Di Matteo F, Smaldone G, Iraci N, Giofrè SV. Mancuso F, et al. Molecules. 2025 Feb 6;30(3):755. doi: 10.3390/molecules30030755. Molecules. 2025. PMID: 39942858 Free PMC article. Review.

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Development of peptide epoxyketones as selective immunoproteasome inhibitors

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Development of peptide epoxyketones as selective immunoproteasome inhibitors

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