Identification of Novel <i>β</i> ‐Lactam Derivatives as Proteasome Inhibitors for Antitumor Therapy

A series of dipeptidic proteasome inhibitors with β-lactam as the C-terminus was designed and synthesized. Biochemical evaluations of their effects on chymotrypsin-like (CT-L) activity revealed that some of them had inhibitory activity against the proteasome, with IC<sub>50</sub> values in the micromolar range. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further selected for antiproliferative assays toward multiple cancer cell lines, with compounds 66 and 78 demonstrating activity against RS4;11 cells and IC<sub>50</sub> values of less than 1 μM. Additionally, cellular mechanistic studies indicated that these effects were linked to their ability to inhibit proteasome signal pathways and to induce apoptosis in RS4;11 cells, as demonstrated by flow cytometry. Collectively, these results illustrate that compound 66 is a potent proteasome inhibitor with significant potential as an antitumor agent.

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Publication Details

Journal
Archiv der Pharmazie
Published
2025-11-01
DOI
https://doi.org/10.1002/ardp.70136
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.00

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Identification of Novel β ‐Lactam Derivatives as Proteasome Inhibitors for Antitumor Therapy

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Archiv der Pharmazie
Ubiquitin and proteasome pathways
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Identification of Novel β ‐Lactam Derivatives as Proteasome Inhibitors for Antitumor Therapy

Jingjing Sun, Li Liao, Liping Fu, Limin Kong, Jianjun Xi, Lu Zhang, Jiankang Zhang, Tong Qiao, Lixin Gao, Yubo Zhou, Yu Cao, Gaoya Xu
article en

Abstract

A series of dipeptidic proteasome inhibitors with β-lactam as the C-terminus was designed and synthesized. Biochemical evaluations of their effects on chymotrypsin-like (CT-L) activity revealed that some of them had inhibitory activity against the proteasome, with IC<sub>50</sub> values in the micromolar range. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further selected for antiproliferative assays toward multiple cancer cell lines, with compounds 66 and 78 demonstrating activity against RS4;11 cells and IC<sub>50</sub> values of less than 1 μM. Additionally, cellular mechanistic studies indicated that these effects were linked to their ability to inhibit proteasome signal pathways and to induce apoptosis in RS4;11 cells, as demonstrated by flow cytometry. Collectively, these results illustrate that compound 66 is a potent proteasome inhibitor with significant potential as an antitumor agent.

Archiv der PharmazieVol. 358(11)
Zhejiang Chinese Medical University (CN), Shaoxing University (CN), Chinese Academy of Sciences (CN), Shanghai Institute of Materia Medica (CN), Hangzhou Xixi hospital (CN), Shaoxing People's Hospital (CN), Hangzhou Children's Hospital (CN), First Affiliated Hospital Zhejiang University (CN), Hangzhou City University
National Natural Science Foundation of China, Zhejiang Medical Association, Zhejiang Pharmaceutical Association, Natural Science Foundation of Zhejiang Province
Openalex Percentile: Top 68%
Ubiquitin and proteasome pathways
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