2. Academic Validation
  3. Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4

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

  • Eur J Med Chem. 2025 Apr 15:288:117410. doi: 10.1016/j.ejmech.2025.117410.
Danni Rao 1,  Yiting Wang 2,  Xiaolong Yang 1,  Zhiwen Chen 2,  Feifei Wu 1,  Ran Ren 2,  Yaoliang Sun 3,  Yuanhui Lai 4,  Lijie Peng 2,  Lei Yu 5,  Zhang Zhang 6,  Shilin Xu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Department of Thyroid and Breast Surgery, Guangdong Second Provincial General Hospital, Jinan University, China.
  • 5 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. Electronic address: yulei31@tongji.edu.cn.
  • 6 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China; Department of Thyroid and Breast Surgery, Guangdong Second Provincial General Hospital, Jinan University, China. Electronic address: zzmoxue@163.com.
  • 7 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: slxu@simm.ac.cn.
PMID: 39978110 DOI: 10.1016/j.ejmech.2025.117410
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.

Keywords

Degrader; Demethylase; KDM4; PROTAC.

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