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Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor

  • Min Jae Jeon
    Min Jae Jeon
    Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
    Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
    More by Min Jae Jeon
  • Hyelim Lee
    Hyelim Lee
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    Department of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
    More by Hyelim Lee
  • Jeehee Lee
    Jeehee Lee
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    Department for HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
    More by Jeehee Lee
  • Soo Yeon Baek
    Soo Yeon Baek
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
  • Donghee Lee
    Donghee Lee
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    More by Donghee Lee
  • Seongman Jo
    Seongman Jo
    Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
    Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
    More by Seongman Jo
  • Joo-Youn Lee
    Joo-Youn Lee
    Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
    More by Joo-Youn Lee
  • Miso Kang
    Miso Kang
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    Department of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
    More by Miso Kang
  • Hee Ra Jung
    Hee Ra Jung
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
    More by Hee Ra Jung
  • Soo Bong Han
    Soo Bong Han
    Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
    Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
    More by Soo Bong Han
  • Nam-Jung Kim
    Nam-Jung Kim
    Department of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
    Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
    More by Nam-Jung Kim
  • Sanghee Lee*
    Sanghee Lee
    Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
    Department for HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
    *Email: [email protected]. Tel.: +82-2-958-5138. Fax: +82-2-958-7034.
    More by Sanghee Lee
  • , and 
  • Hyejin Kim*
    Hyejin Kim
    Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
    *Email: [email protected]. Tel.: (+82)-42-860-7130. Fax: +82-42-860-7160.
    More by Hyejin Kim
Cite this: J. Med. Chem. 2022, 65, 7, 5407–5432
Publication Date (Web):March 22, 2022
https://doi.org/10.1021/acs.jmedchem.1c01795
Copyright © 2022 American Chemical Society

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    Abstract

    Abstract Image

    Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01795.

    • Experimental procedures and results for biological assays and molecular docking studies and synthetic procedures and characterization data for presented compounds, including the spectral copies of the 1H and 13NMR spectra (PDF)

    • Molecular formula strings for synthetic compounds (CSV)

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    Cited By

    This article is cited by 6 publications.

    1. Yeonguk Cho, Miso Kang, Su Hyun Ji, Hee Jin Jeong, Jae Eun Jung, Do Hee Oh, Sunyoung Park, Yong-Yea Park, Junghwan Choi, Sungjoon Kim, Nam-Jung Kim, Duck-Hyung Lee, Chan Sun Park, Seo-Jung Han, Sanghee Lee, Junwon Choi. Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy. Journal of Medicinal Chemistry 2023, 66 (22) , 15141-15170. https://doi.org/10.1021/acs.jmedchem.3c01061
    2. Nan-Nan Chen, Han Zhang, Qiang-Sheng Zhu, Ting Zeng, Wei Dai, Ye-Ling Zhou, Guo-Feng Xin, Bei-Duo Wu, Si-Jia Gong, Zheng-Yu Jiang, Qi-Dong You, Xiao-Li Xu. Development of Orally Bioavailable Amidobenzimidazole Analogues Targeting Stimulator of Interferon Gene (STING) Receptor. Journal of Medicinal Chemistry 2023, 66 (8) , 5584-5610. https://doi.org/10.1021/acs.jmedchem.2c02046
    3. Xi Feng, Lixia Pan, Zhiyu Qian, Dongyu Liu, Xin Guan, Li Feng, Bin Song, Xi Xu, Ninghua Tan, Yi Ma, Zhiyu Li, Zhe Wang, Jinlei Bian. Discovery of Selenium-Containing STING Agonists as Orally Available Antitumor Agents. Journal of Medicinal Chemistry 2022, 65 (22) , 15048-15065. https://doi.org/10.1021/acs.jmedchem.2c00634
    4. Zdeněk Vavřina, Pavla Perlíková, Nemanja Milisavljević, Florian Chevrier, Miroslav Smola, Joshua Smith, Milan Dejmek, Vojtěch Havlíček, Miloš Buděšínský, Radek Liboska, Lenka Vaneková, Jiří Brynda, Evzen Boura, Pavlína Řezáčová, Michal Hocek, Gabriel Birkuš. Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists. Journal of Medicinal Chemistry 2022, 65 (20) , 14082-14103. https://doi.org/10.1021/acs.jmedchem.2c01305
    5. Junwon Choi. Small molecule ectonucleotide pyrophosphatase/phosphodiesterase 1 inhibitors in cancer immunotherapy for harnessing innate immunity. Bulletin of the Korean Chemical Society 2023, 44 (2) , 88-99. https://doi.org/10.1002/bkcs.12646
    6. Ruilei Huang, Qian Ning, Jihui Zhao, Xuhong Zhao, Luting Zeng, Yi Yi, Shengsong Tang. Targeting STING for cancer immunotherapy: From mechanisms to translation. International Immunopharmacology 2022, 113 , 109304. https://doi.org/10.1016/j.intimp.2022.109304

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