2. Academic Validation
  3. Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation

Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation

  • Eur J Med Chem. 2022 Jan 15:228:113954. doi: 10.1016/j.ejmech.2021.113954.
Jinxin Che 1,  Canliang Ma 1,  Jialiang Lu 1,  Binhui Chen 1,  Qiuqiu Shi 1,  Xinxin Jin 1,  Rui Song 2,  Fan Xu 1,  Lishe Gan 3,  Jingya Li 4,  Yongzhou Hu 1,  Xiaowu Dong 5
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 3 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong, 529020, China.
  • 4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China. Electronic address: [email protected].
PMID: 34772527 DOI: 10.1016/j.ejmech.2021.113954
Abstract

Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis.

Keywords

4E-BP1; Glucose homeostasis; L6 myotubes; Phenotypic screening; Proteomic analysis; Seneciobipyrrolidine.

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