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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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