2. Academic Validation
  3. Discovery of bardoxolone derivatives as novel orally active necroptosis inhibitors

Discovery of bardoxolone derivatives as novel orally active necroptosis inhibitors

  • Eur J Med Chem. 2021 Feb 15;212:113030. doi: 10.1016/j.ejmech.2020.113030.
Yuanyuan Wang 1,  Hao Ma 2,  Jiaxuan Huang 3,  Zhengguang Yao 4,  Jianqiang Yu 5,  Wannian Zhang 3,  Lichao Zhang 6,  Zhibin Wang 7,  Chunlin Zhuang 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China; Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai, 200071, China.
  • 2 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China; Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nan Wei Road, Beijing, 100050, China.
  • 3 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
  • 4 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 5 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
  • 6 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai, 200071, China. Electronic address: [email protected].
  • 7 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
  • 8 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: [email protected].
PMID: 33248849 DOI: 10.1016/j.ejmech.2020.113030
Abstract

Necroptosis is a form of programmed cell death that contributes to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury. In this study, bardoxolone (CDDO, 7) was an inhibitor of Necroptosis identified from an in-house natural product library. Further optimization led to identify a more potent analogue 20. Compound 20 could effectively protect against Necroptosis in human and mouse cells. The antinecroptotic effect could also be synergized with other Necroptosis inhibitors. It blocked necrosome formation by targeting HSP90 to inhibit the phosphorylation of RIPK1 and RIPK3 in necroptotic cells. In vivo, this compound was orally active to alleviate TNF-induced systemic inflammatory response syndrome (SIRS) and cerebral I/R injury. Our results suggested that 20 could be a lead compound for discovering Necroptosis inhibitors in I/R treatment.

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