Discovery of second generation heat shock protein 110 (HSP110) inhibitors for potential treatment of colorectal cancer

Li Xu; Yuan Wang; Xingrui He; Yuan Gao; Frédéric Lirussi; Yi Zhou; Carmen Garrido; Hang Zhang; Tian Xie; Xiang-Yang Ye

European Journal of Medicinal Chemistry Reports (Apr 2023)

Discovery of second generation heat shock protein 110 (HSP110) inhibitors for potential treatment of colorectal cancer

Li Xu,
Yuan Wang,
Xingrui He,
Yuan Gao,
Frédéric Lirussi,
Yi Zhou,
Carmen Garrido,
Hang Zhang,
Tian Xie,
Xiang-Yang Ye

Affiliations

Li Xu: School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
Yuan Wang: School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
Xingrui He: School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
Yuan Gao: Institute of Chinese Materia Medical, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Frédéric Lirussi: INSERM UMR 1231, Labex LipSTIC, Faculty of Medicine, University of Bourgogne, 21000, Dijon, France; University of Bourgogne Franche-Comté, 25056, Besançon, France
Yi Zhou: School of Basic Medicine, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
Carmen Garrido: INSERM UMR 1231, Labex LipSTIC, Faculty of Medicine, University of Bourgogne, 21000, Dijon, France; University of Bourgogne Franche-Comté, 25056, Besançon, France; Cancer Center Georges François Leclerc, 21000, Dijon, France; Corresponding author. INSERM UMR 1231, Labex LipSTIC, Faculty of Medicine, University of Bourgogne, 21000, Dijon, France.
Hang Zhang: School of Basic Medicine, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China; Corresponding author. School of Basic Medicine, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
Tian Xie: School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Corresponding author. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
Xiang-Yang Ye: School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Corresponding author. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.

Journal volume & issue: Vol. 7
p. 100103

Abstract

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Heat shock protein 110 (HSP110) is an emerging biological target for development of drug to treat colorectal cancer. In the present study, we designed and synthesized a series of novel small-molecule inhibitors of HSP110 based on previously reported HSP110 modulator (hit 1). Among the novel compounds, molecule 7 exhibited the most improved biological activity in vitro and anticancer efficacy in vivo. It exerted greater anti-proliferative potency against several colorectal cancer cells including HCT116 and SW480 with IC50 values of 11.59 μM and 6.05 μM, respectively. Molecular docking experiment of 7 with HSP110 protein revealed it bound well with the target in the similar way as compound 1. Mechanistic studies revealed that 7 effectively inhibited STAT3 activity and the expression of STAT3 downstream genes, VEGF, MMP7, MMP9. Moreover, 7 significantly abolished IL-6-induced epithelial-mesenchymal transition (EMT) in HCT116 and SW480 cells. Finally, 7 exhibited stronger tumor growth inhibition than lead compound 1 at the dose of 5 mg/kg (i.p.) in an in vivo HCT116 cells xenografted nude mice model. Taken together, we identified 7 as 2nd generation of HSP110 inhibitor which exerts remarkable anti-colorectal cancer activities. This compound might serve as a new lead for developing anti-cancer drugs to treat colorectal cancer.

Published in European Journal of Medicinal Chemistry Reports

ISSN: 2772-4174 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Pharmacy and materia medica; Medicine: Other systems of medicine
Website: https://www.journals.elsevier.com/european-journal-of-medicinal-chemistry-reports

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