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

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外文摘要：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 dea-cetylases(HADC1-11 and SIRT1-3)at concentrations up to 100 μmol/L.The allosteric site and the mo-lecular 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 pancre-atic cancer.

外文关键词：

SIRT6InhibitorAllostericSelectivityCocrystalPancreatic cancer metastasis

作者：

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

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作者单位：

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 General Surgery,Huashan Hospital,Cancer Metastasis Institute,Fudan University Shanghai 200040,China

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

Department of Assisted Reproduction,Shanghai Ninth People,s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

College of Pharmacy,Ningxia Medical University,Yinchuan 750004,China

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

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基金：

国家重点研发计划国家自然科学基金国家自然科学基金国家自然科学基金Innovative Research Team of High-Level Local Universities in Shanghai中国博士后科学基金

项目编号：

2022YFF1203005222370058190345882273425SHSMU-ZDCX202127002019M660090

出版年：

2024

DOI：

10.1016/j.apsb.2023.11.014

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(3)

参考文献量55