Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors

  • Bioorg Med Chem. 2023 Oct 14:95:117502. doi: 10.1016/j.bmc.2023.117502.
Po-Wei Chang  1 ,  Jing-Ya Wang  1 ,  Wan-Ping Wang  1 ,  Wei-Cheng Huang  1 ,  Mine-Hsine Wu  1 ,  Jen-Shin Song  1 ,  Liuh-Yow Chen  2 ,  Chun-Wei Tung  1 ,  Ya-Hui Chi  3 ,  Shau-Hua Ueng  4
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
  • 2. Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, ROC.
  • 3. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC. Electronic address: [email protected].
  • 4. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC; School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC. Electronic address: [email protected].
PMID: 37866089 DOI: 10.1016/j.bmc.2023.117502
Abstract

A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STINGR232 knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents.

Keywords
Cyclic AMP-GMP synthase; Interferon regulatory factor 3; STING inhibitor; Stimulator of interferon genes; cGAS-STING pathway.
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