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Design, synthesis, and STING-agonistic activity of benzo[b]thiophene-2-carboxamide derivatives

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Abstract

STING is an important immune-associated protein that localizes in the endoplasmic reticulum membrane. Upon being activated by its agonists, STING triggers the IRF and NF-κB pathways, which generates type I interferons and proinflammatory cytokines, and ultimately primes the innate immune responses to achieve valid antitumor efficacy. We designed and synthesized a series of benzo[b]thiophene-2-carboxamide derivatives. Through STING-agonistic activity evaluation, compounds 12d and 12e exhibited marginal human STING-activating activities. Western blot analysis demonstrated that both 12d and 12e treatment increased the phosphorylation of the downstream signaling molecules (TBK1 and IRF3) of STING. The proposed binding mode of 12d/12e and STING protein displayed that two canonical hydrogen bonds, a π-π stacking interaction, as well as a π-cation interaction formed between the agonist and the CDN-binding domain of STING protein.

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Acknowledgements

We thank Shanghai Institute of Materia Medica (no. CASIMM0120215010), the Lingang Laboratory (No. LG202103-02-08), Science and Technology Commission of Shanghai Municipality (No. 21ZR1475700) for their financial support.

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Author notes

  1. Rongyao Zhou and Xiyuan Wang contributed equally to this work.

Authors and Affiliations

  1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China

    Rongyao Zhou, Zhengsheng Zhan & ·Wenhu Duan

  2. Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, People’s Republic of China

    Rongyao Zhou, Zhengsheng Zhan & ·Wenhu Duan

  3. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, People’s Republic of China

    Xiyuan Wang & Deqiang Zhang

  4. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, People’s Republic of China

    Zhengsheng Zhan & ·Wenhu Duan

Authors
  1. Rongyao Zhou
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  2. Xiyuan Wang
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Contributions

RZ synthesized the compounds, performed the molecular docking study, and prepared the manuscript. XW and DZ conducted the biological assays of the compounds, and also prepared the manuscript. ZZ and WD designed and supervised this work and reviewed the manuscript.

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Correspondence to Zhengsheng Zhan or ·Wenhu Duan.

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Zhou, R., Wang, X., Zhang, D. et al. Design, synthesis, and STING-agonistic activity of benzo[b]thiophene-2-carboxamide derivatives. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10736-1

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