Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI:10.1021/acs.jmedchem.5c01315

Zhongli Xu,Dmitry Pokushalov,Md Kabir,Youngeun Lee,Mrittika Chattopadhyay,Edmund C Jenkins,Cessarina Choo,H Ümit Kaniskan,Doris Germain,Jian Jin

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引用次数: 0

Abstract

Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound 9 (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound 9 induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound 9 therefore add to the expanding arsenal of imipridones to target ClpP in cancer.

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靶向线粒体蛋白酶ClpP的抗癌治疗。

癌细胞依赖线粒体重编程来生长，但这会增加活性氧（ROS），增加对蛋白质质量控制（PQC）修复机制的依赖。线粒体蛋白质组通过由伴侣蛋白和蛋白酶组成的强大PQC来维持，包括线粒体基质蛋白酶酪蛋白溶酶P （ClpP）。ClpP最近成为抗癌的潜在治疗靶点。值得注意的是，吡普利酮作为ClpP激动剂，通过抑制线粒体电子传递链（ETC）功能显示出强大的抗癌活性。在这项研究中，我们开发了新一代ClpP激动剂化合物9 (MS6076)，与吡普利酮ONC212相比，它在乳腺癌模型中表现出更强的ClpP结合，更有效的线粒体ETC破坏和致残性。此外，我们发现化合物9可诱导耐ONC212的癌细胞死亡。因此，化合物9的发现和表征增加了吡普利酮在癌症中针对ClpP的扩展库。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.