2. Academic Validation
  3. Discovery of N-alkyl-N-benzyl thiazoles as novel TRPC antagonists for the treatment of glioblastoma multiforme

Discovery of N-alkyl-N-benzyl thiazoles as novel TRPC antagonists for the treatment of glioblastoma multiforme

  • Eur J Med Chem. 2024 Feb 5:265:116066. doi: 10.1016/j.ejmech.2023.116066.
Shanshan Wang 1,  Xiaoxue Li 2,  Yuemiao Hu 1,  Lin Wang 1,  Guangyao Lv 1,  Yuxin Feng 1,  Ziqiang Sun 2,  Zhengyu Cao 3,  Yi Liu 4,  Hongbo Wang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
  • 2 School of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China.
  • 3 State Key Laboratory of Natural Medicines & Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 School of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China. Electronic address: liuyi@ytu.edu.cn.
  • 5 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. Electronic address: hongbowangyt@gmail.com.
PMID: 38185057 DOI: 10.1016/j.ejmech.2023.116066
Abstract

Glioblastoma multiforme represents a substantial clinical challenge. Transient receptor potential channel (TRPC) antagonists might provide new therapeutic options for this aggressive Cancer. In this study, a series of N-alkyl-N-benzoyl and N-alkyl-N-benzyl thiazoles were designed and prepared using a scaffold-hopping strategy and evaluated as TRPC6 antagonists. This resulted in the discovery of 15g, a potent TRPC Antagonist that exhibited suitable inhibitory micromolar activities against TRPC3, TRPC4, TRPC5, TPRC6, and TRPC7 and displayed noteworthy anti-glioblastoma efficacy in vitro against U87 cell lines. In addition, 15g featured an acceptable pharmacokinetic profile and exhibited better in vivo potency (25 mg/kg/d) than the frontline therapeutic agent temozolomide (50 mg/kg/d) in xenograft models. Taken together, the TRPC Antagonist 15g represents a promising lead compound for developing new anti-glioblastoma agents.

Keywords

Antiproliferative; Glioblastoma multiforme; In vivo efficacy; N-alkyl-N-benzyl thiazoles; TRPC antagonist.

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