Synthesis and anticancer activity of parthenolide-based PROTACs for IKKβ degradation

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-02-05 DOI:10.1016/j.bmcl.2026.130571

Zhenxi Su , Yiwu Wu , Yijie Su , Yuhan He , Jieyin Liu , Deng-Gao Zhao

{"title":"Synthesis and anticancer activity of parthenolide-based PROTACs for IKKβ degradation","authors":"Zhenxi Su , Yiwu Wu , Yijie Su , Yuhan He , Jieyin Liu , Deng-Gao Zhao","doi":"10.1016/j.bmcl.2026.130571","DOIUrl":null,"url":null,"abstract":"<div><div>Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound <strong>8</strong> exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that <strong>8</strong> acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC<sub>50</sub> = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with <strong>8</strong> was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130571"},"PeriodicalIF":2.2000,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X26000387","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/2/5 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound 8 exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that 8 acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC₅₀ = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with 8 was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.

Abstract Image

查看原文本刊更多论文

基于parthenolide的IKKβ降解PROTACs的合成及抗癌活性研究

Parthenolide是一种天然的IκB激酶β (IKKβ)抑制剂。将其转化为PROTAC（蛋白水解靶向嵌合体）可能会提高药理学疗效。在此，我们报道了一系列新的基于parthenolide的PROTACs的设计，合成和生物学评价。其中，化合物8对三阴性乳腺癌MDA-MB-231细胞表现出较强的抗增殖活性。机制研究表明，8作为一种有效的IKKβ降解剂，通过泛素-蛋白酶体系统诱导降解（DC50 = 7.15 μM，在10 μM下降解率为91.24%）。此外，在MDA-MB-231细胞中，8与显著的细胞凋亡和g1期细胞周期阻滞有关。这项工作提供了初步证据，证明parthenolide支架可以用于靶向蛋白质降解，支持未来开发ikk β定向降解物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.