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

Jinyun Dong; Jing Yang; Wenkai Yu; Haobin Li; Maohua Cai; Jing-Li Xu; Han-Dong Xu; Yun-Fu Shi; Xiaoqing Guan; Xiang-Dong Cheng; Jiang-Jiang Qin

doi:10.1080/14756366.2022.2100366

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2004-2016. doi: 10.1080/14756366.2022.2100366.

Authors

Jinyun Dong^{1

2

3

4}, Jing Yang⁴, Wenkai Yu⁴, Haobin Li⁴, Maohua Cai⁴, Jing-Li Xu⁵, Han-Dong Xu⁵, Yun-Fu Shi⁵, Xiaoqing Guan^{1

2

3}, Xiang-Dong Cheng^{1

2

3}, Jiang-Jiang Qin^{1

2

3

4}

Affiliations

¹ The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
² Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou , China.
³ Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou , China.
⁴ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
⁵ The First Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, China.

Abstract

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.

Keywords: Benzochalcone analogues; STAT3; gastric cancer.

MeSH terms

Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chalcones* / pharmacology
Humans
Molecular Targeted Therapy
Phosphorylation / drug effects
STAT3 Transcription Factor* / metabolism
Signal Transduction / drug effects
Stomach Neoplasms* / drug therapy

Substances

Chalcones
STAT3 Transcription Factor
STAT3 protein, human

Grants and funding

This research was supported by grants from Zhejiang Provincial Natural Science Foundation of China [LR21H280001, LQ21B020003, and Q22H287247], National Natural Science Foundation of China [82103967 and 81903842], Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province [2022E10021], Program of Zhejiang Provincial TCM Sci-tech Plan [2020ZZ005], and China Postdoctoral Science Foundation [2021M692873]. Also, we thank Dr. Guoxun Zheng for molecular dynamics (MD) simulation.