2. Academic Validation
  3. 13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents

  • Eur J Med Chem. 2024 Apr 15:270:116312. doi: 10.1016/j.ejmech.2024.116312.
Yaxu Wang 1,  Liwei Gu 2,  Jichong Li 1,  Ruqi Wang 1,  Yuan Zhuang 1,  Xiangyun Li 1,  Xinye Wang 1,  Junzhe Zhang 2,  Qingbo Liu 3,  Jigang Wang 4,  Shao-Jiang Song 5
Affiliations

Affiliations

  • 1 Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 2 Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China.
  • 3 Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: liuqingbolily@163.com.
  • 4 Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China. Electronic address: jgwang@icmm.ac.cn.
  • 5 Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: songsj99@163.com.
PMID: 38552425 DOI: 10.1016/j.ejmech.2024.116312
Abstract

Ingenol Diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of Cancer were screened and some derivatives showed superior anti-non-small cell lung Cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, CA2+ release function was affected, causing mitochondrial CA2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced Mitophagy and Ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

Keywords

13-Oxyingenol dodecanoate; Ferroptosis; Mitophagy; Modification; Photoaffinity probe; TMBIM6.

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