Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

Xinyuan Xu; Qian Zhang; Xufeng Wang; Jing Jin; Chengwei Wu; Li Feng; Xiuyan Yang; Mingzhu Zhao; Yingyi Chen; Shaoyong Lu; Zhen Zheng; Xiaobing Lan; Yi Wang; Yan Zheng; Xuefeng Lu; Qiufen Zhang; Jian Zhang

Acta Pharmaceutica Sinica B (Mar 2024)

Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

Xinyuan Xu,
Qian Zhang,
Xufeng Wang,
Jing Jin,
Chengwei Wu,
Li Feng,
Xiuyan Yang,
Mingzhu Zhao,
Yingyi Chen,
Shaoyong Lu,
Zhen Zheng,
Xiaobing Lan,
Yi Wang,
Yan Zheng,
Xuefeng Lu,
Qiufen Zhang,
Jian Zhang

Affiliations

Xinyuan Xu: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Medicinal Chemistry and BioinformaticsCenter, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Qian Zhang: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Medicinal Chemistry and BioinformaticsCenter, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xufeng Wang: Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
Jing Jin: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230026, China
Chengwei Wu: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Medicinal Chemistry and BioinformaticsCenter, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Li Feng: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Medicinal Chemistry and BioinformaticsCenter, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
Xiuyan Yang: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Mingzhu Zhao: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
Yingyi Chen: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Shaoyong Lu: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Zhen Zheng: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xiaobing Lan: College of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
Yi Wang: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230026, China; Corresponding authors.
Yan Zheng: Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Corresponding authors.
Xuefeng Lu: Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Corresponding authors.
Qiufen Zhang: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Corresponding authors.
Jian Zhang: State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Medicinal Chemistry and BioinformaticsCenter, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Corresponding authors.

Journal volume & issue: Vol. 14, no. 3
pp. 1302 – 1316

Abstract

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Pancreatic cancer, one of the most aggressive malignancies, has no effective treatment due to the lack of targets and drugs related to tumour metastasis. SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer. However, highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered. Here, we developed a novel SIRT6 allosteric inhibitor, compound 11e, with maximal inhibitory potency and an IC50 value of 0.98 ± 0.13 μmol/L. Moreover, compound 11e exhibited significant selectivity against other histone deacetylases (HADC1‒11 and SIRT1‒3) at concentrations up to 100 μmol/L. The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses. Importantly, we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis. To our knowledge, this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer. It not only provides a promising lead compound for subsequent inhibitor development targeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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