1. Academic Validation
  2. AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo

AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo

  • Biochem Biophys Res Commun. 2016 Sep 9;478(1):330-336. doi: 10.1016/j.bbrc.2016.01.167.
Yu Xi 1 Jianhua Niu 2 Yun Shen 3 Dongmei Li 4 Xinyu Peng 5 Xiangwei Wu 6
Affiliations

Affiliations

  • 1 Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China.
  • 2 Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China.
  • 3 Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China.
  • 5 Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China. Electronic address: [email protected].
  • 6 Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China. Electronic address: [email protected].
Abstract

The AGC kinase family is important cell proliferation and survival. Dysregulation of this family contributes to gastric Cancer progression. Here, we evaluated the potential activity of AT13148, a first-in-class multi-AGC kinase inhibitor, against gastric Cancer cells. Our results showed that AT13148 exerted potent cytotoxic and anti-proliferative activities against a panel human gastric Cancer cell lines (HGC-27, AGS, SNU-601, N87 and MKN-28), possibly via inducing Cancer cell apoptotic death. Apoptosis inhibition by the Caspase blockers dramatically attenuated AT13148-caused cytotoxicity against gastric Cancer cells. Intriguingly, same AT13148 treatment was not cytotoxic/pro-apoptotic to the non-cancerous human gastric epithelial GEC-1 cells. At the signaling level, AT13148 treatment in gastric Cancer cells dramatically suppressed activation of multiple AGC kinases, including Akt (at p-Thr-308), p70S6 kinase (p70S6K), glycogen synthase kinase 3β (GSK-3β) and p90 ribosomal S6 kinase (RSK). Our in vivo studies demonstrated that daily oral gavage of AT13148 at well-tolerated doses significantly inhibited HGC27 xenograft tumor growth in nude mice. AGC activity was also dramatically decreased in AT13148-administrated HGC27 tumors. Therefore, targeting AGC kinases by AT13148 demonstrates superior anti-gastric Cancer activity both in vitro and in vivo. The preclinical results of this study support the progression of this molecule into future evaluation as a valuable anti-gastric Cancer candidate.

Keywords

AGC kinases; AT13148; Anti-tumor activity and signaling; Gastric cancer.

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