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

Biochemical and Biophysical Research Communications
Yu XiXiangwei Wu

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. ...Continue Reading

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Citations

Jun 21, 2017·Small GTPases·Jordan M ThompsonOlga V Razorenova
Apr 15, 2020·Metabolomics : Official Journal of the Metabolomic Society·Akos PalFlorence I Raynaud
Jul 4, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert McLeodUdai Banerji
Jul 30, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Graziella Ribeiro de SousaMaría Sol Brassesco
Sep 21, 2021·Physiological Reviews·Eva Crosas-MolistVictoria Sanz-Moreno

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