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Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

  • Zisheng Kang
    Zisheng Kang
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Zisheng Kang
  • Cong Wang
    Cong Wang
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Cong Wang
  • Yu Tong
    Yu Tong
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Yu Tong
  • Yanyi Li
    Yanyi Li
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Yanyi Li
  • Yi Gao
    Yi Gao
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Yi Gao
  • Siyuan Hou
    Siyuan Hou
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Siyuan Hou
  • Meixi Hao
    Meixi Hao
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Meixi Hao
  • Xiaolin Han
    Xiaolin Han
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Xiaolin Han
  • Bin Wang
    Bin Wang
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Bin Wang
  • Qianqian Wang
    Qianqian Wang
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    More by Qianqian Wang
  • , and 
  • Can Zhang*
    Can Zhang
    State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
    *Email: [email protected]. Tel/Fax: 86-25-83271171.
    More by Can Zhang
Cite this: J. Med. Chem. 2021, 64, 1, 629–643
Publication Date (Web):December 31, 2020
https://doi.org/10.1021/acs.jmedchem.0c01197
Copyright © 2020 American Chemical Society

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    Abstract

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    In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs in vitro. In vivo, compound I5 combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01197.

    • (Table S1) Cell toxicity of all target compounds against LTC-14; (Figure S1) cell toxicity of representative compounds against DSL-6A/C1 cells; (Figure S2) relative BLI intensities of mice that received different treatments; (Figure S3) inhibition rate of tumor growth after tumor-bearing mice received different treatments; (Figure S4) relative fluorescence intensities of α-SMA after mice received different treatments; (Figure S5) survival percentages of mice that received different treatments; (Figure S6) in vivo hypercalcemic effects in the orthotopic transplantation pancreatic cancer model; NMR spectra information; HPLC traces; and 1H NMR and 13C NMR spectra (PDF)

    • Molecular Formula Strings (CSV)

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    Cited By

    This article is cited by 11 publications.

    1. Tongfu Yang, Zhenlei Zhang, Juzheng Zhang, Yanping Li, Wenjuan Li, Hong Liang, Feng Yang. Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer. Journal of Medicinal Chemistry 2023, 66 (1) , 793-803. https://doi.org/10.1021/acs.jmedchem.2c01684
    2. Zhennan Yuan, Yingpu Li, Sifan Zhang, Xueying Wang, He Dou, Xi Yu, Zhiren Zhang, Shanshan Yang, Min Xiao. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Molecular Cancer 2023, 22 (1) https://doi.org/10.1186/s12943-023-01744-8
    3. Rui Liang, Guanbin Song. Matrix stiffness-driven cancer progression and the targeted therapeutic strategy. Mechanobiology in Medicine 2023, 1 (2) , 100013. https://doi.org/10.1016/j.mbm.2023.100013
    4. Kai Xing, Yue Wu, Fei Gao, Yupeng Dai, Chun Guan, Yu Tong, Yi Gao, Cong Wang, Can Zhang. Design, synthesis and anti-hepatic fibrosis activity of novel diphenyl vitamin D receptor agonists. European Journal of Medicinal Chemistry 2023, 258 , 115596. https://doi.org/10.1016/j.ejmech.2023.115596
    5. Pratibha Malhotra, Ranjith Palanisamy, Jose A. Caparros-Martin, Marco Falasca. Bile Acids and Microbiota Interplay in Pancreatic Cancer. Cancers 2023, 15 (14) , 3573. https://doi.org/10.3390/cancers15143573
    6. Guixian Zhang, Xiumei Zhao, Jun Cai, Sainan Li, Xijing Li, Wenchang Li, Pengcheng Shi, Dawei Liu, Duo Zheng, Ting Zhang, Renrui Feng, Hongbin Liu. XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP. Journal of Ethnopharmacology 2023, 300 , 115689. https://doi.org/10.1016/j.jep.2022.115689
    7. Weijian Kong, Zhengsheng Liu, Mengnan Sun, Huiqin Liu, Chao Kong, Jie Ma, Rui Wang, Feng Qian. Synergistic autophagy blockade and VDR signaling activation enhance stellate cell reprogramming in pancreatic ductal adenocarcinoma. Cancer Letters 2022, 539 , 215718. https://doi.org/10.1016/j.canlet.2022.215718
    8. Meifang Zheng, Runping Gao. Vitamin D: A Potential Star for Treating Chronic Pancreatitis. Frontiers in Pharmacology 2022, 13 https://doi.org/10.3389/fphar.2022.902639
    9. Francesca Coperchini, Alessia Greco, Laura Croce, Elena Petrosino, Beatrice Grillini, Flavia Magri, Luca Chiovato, Mario Rotondi. Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion. Frontiers in Endocrinology 2022, 13 https://doi.org/10.3389/fendo.2022.876397
    10. Daoyan Wei, Liang Wang, Xiangsheng Zuo, Robert S. Bresalier. Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer. Cancers 2021, 13 (11) , 2716. https://doi.org/10.3390/cancers13112716
    11. David J. Easty, Christine J. Farr, Bryan T. Hennessy. New Roles for Vitamin D Superagonists: From COVID to Cancer. Frontiers in Endocrinology 2021, 12 https://doi.org/10.3389/fendo.2021.644298

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