Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-02-19 DOI:10.1016/j.ejmech.2025.117410

Danni Rao , Yiting Wang , Xiaolong Yang , Zhiwen Chen , Feifei Wu , Ran Ren , Yaoliang Sun , Yuanhui Lai , Lijie Peng , Lei Yu , Zhang Zhang , Shilin Xu

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Abstract

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.