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Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment.

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机构： [1]School of Medicine, Zhejiang University City College, Hangzhou, 310015, China [2]College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China [3]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China [4]University of Chinese Academy of Sciences, Beijing, 100049, China [5]Department of Pharmacy, Shaoxing TCM Hospital Affiliated to Zhejiang Chinese Medical University, Shaoxing, 312000, China [6]School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China [7]Zhongshan Institute for Drug Discovery, Shanghai Institute of Metria Medica, Chinese Academy of Sciences, Guangdong, 528400, China [8]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China

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关键词： Metabolism Design Proteasome inhibitors Non-covalent Multiple myeloma

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A series of novel non-covalent peptidomimetic proteasome inhibitors possessing bulky group at the C-terminus and N-alkylation at the N-terminus were designed with the aim to increase metabolic stabilities in vivo. All the target compounds were screened for their inhibitory activities against human 20S proteasome, and most analogs exhibited notable potency compared with the positive control bortezomib with IC50 values lower than 10 nM, which also displayed potent cytotoxic activities against multiple myeloma (MM) cell lines and human acute myeloid leukemia (AML) cells. Furthermore, whole blood stability and in vivo proteasome inhibitory activity experiments of selected compounds were conducted for further evaluation, and the representative compound 43 (IC50 = 8.39 ± 2.32 nM, RPMI-8226: IC50 = 15.290 ± 2.281 nM, MM-1S: IC50 = 9.067 ± 3.103 nM, MV-4-11: IC50 = 2.464 ± 0.713 nM) revealed a half-life extension of greater than 9-fold (329.21 min VS 36.79 min) and potent proteasome inhibitory activity in vivo. The positive results confirmed the reliability of the metabolism guided optimization strategy, and the analogs discovered are potential leads for exploring new anti-MM drugs.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2025]版：

大类 | 2 区医学

小类 | 1 区药物化学

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第一作者机构： [1]School of Medicine, Zhejiang University City College, Hangzhou, 310015, China [2]College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

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通讯机构： [3]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China [4]University of Chinese Academy of Sciences, Beijing, 100049, China [7]Zhongshan Institute for Drug Discovery, Shanghai Institute of Metria Medica, Chinese Academy of Sciences, Guangdong, 528400, China [8]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China [*1]State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

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