4.6 Article

Discovery of benzochalcone derivative as a potential antigastric cancer agent targeting signal transducer and activator of transcription 3 (STAT3)

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出版社

TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2022.2100366

关键词

Benzochalcone analogues; STAT3; gastric cancer

资金

  1. Zhejiang Provincial Natural Science Foundation of China [LR21H280001, LQ21B020003, Q22H287247]
  2. National Natural Science Foundation of China [82103967, 81903842]
  3. Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province [2022E10021]
  4. Program of Zhejiang Provincial TCM Sci-tech Plan [2020ZZ005]
  5. China Postdoctoral Science Foundation [2021M692873]

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The study found that the quinolin-6-yl substituted derivative KL-6 effectively inhibited the growth and invasion of gastric cancer cells, and induced apoptosis. The compound also showed anticancer activity in a mouse model of gastric cancer without significant toxicity. Therefore, KL-6 may be a promising candidate for further research and development of gastric cancer treatment drugs.
Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.

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