2. Academic Validation
  3. Discovery of novel peptide-dehydroepiandrosterone hybrids inducing endoplasmic reticulum stress with effective in vitro and in vivo anti-melanoma activities

Discovery of novel peptide-dehydroepiandrosterone hybrids inducing endoplasmic reticulum stress with effective in vitro and in vivo anti-melanoma activities

  • Eur J Med Chem. 2024 Mar 7:269:116296. doi: 10.1016/j.ejmech.2024.116296.
Juan Feng 1,  Yidong Liu 2,  Xia Tian 3,  Chen Shen 1,  Zhiqiang Feng 4,  Jingxu Zhang 1,  Xiangli Yao 1,  Meilin Pu 1,  Xuguang Miao 1,  Lan Ma 1,  Shouxin Liu 5
Affiliations

Affiliations

  • 1 State Key Laboratory Breeding Base-Hebei Key Laboratory of Molecular Chemistry for Drug, Hebei Collaborative Innovation Centre of New Drug Creation, College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, No. 26 Yuxiang Street, Shijiazhuang, 050022, Hebei, China.
  • 2 State Key Laboratory Breeding Base-Hebei Key Laboratory of Molecular Chemistry for Drug, Hebei Collaborative Innovation Centre of New Drug Creation, College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, No. 26 Yuxiang Street, Shijiazhuang, 050022, Hebei, China. Electronic address: [email protected].
  • 3 School of Science, Hebei University of Science and Technology, Shijiazhuang, 050022, Hebei, China.
  • 4 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 5 State Key Laboratory Breeding Base-Hebei Key Laboratory of Molecular Chemistry for Drug, Hebei Collaborative Innovation Centre of New Drug Creation, College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, No. 26 Yuxiang Street, Shijiazhuang, 050022, Hebei, China. Electronic address: [email protected].
PMID: 38467086 DOI: 10.1016/j.ejmech.2024.116296
Abstract

Steroid hybrids have emerged as a type of advantageous compound as they could offer improved pharmacological and pharmaceutical properties. Here, we report a series of novel peptide-dehydroepiandrosterone hybrids, which would effectively induce endoplasmic reticulum stress (ERS) and lead to Apoptosis with outstanding in vitro and in vivo anti-melanoma effects. The lead compound IId among various Steroids conjugated with Peptides and pyridines showed effective in vivo activity in B16 xenograft mice: in medium- and high-dose treatment groups (60 and 80 mg/kg), compound IId would significantly inhibit the growth of tumours by 98%-99% compared to the control group, with the highest survival rate as well. Further mechanism studies showed that compound IId would damage the endoplasmic reticulum and upregulate the ERS markers C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), which could further regulate Caspase and Bcl-2 Family proteins and lead to cell Apoptosis. The compound IId was also proven to be effective in inhibiting B16 cell migration and invasion.

Keywords

Anti-melanoma; B16 xenograft mice study; DHEA derivatives; Endoplasmic reticulum stress induction; Peptidyl steroid; Steroid hybrids; Structure–activity relationship.

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