2. Academic Validation
  3. Discovery of ETI41 and ETI60: novel selective endosomal Toll-like receptor inhibitors for the treatment of autoimmune diseases

Discovery of ETI41 and ETI60: novel selective endosomal Toll-like receptor inhibitors for the treatment of autoimmune diseases

  • Exp Mol Med. 2025 Sep;57(9):1951-1962. doi: 10.1038/s12276-025-01526-w.
Uisuk Jeong # 1 2,  Wang Hee Lee # 2,  Yang Seon Choi # 2,  Muhammad Haseeb 1,  Wook-Young Baek 2,  Ji Hye Han 2,  Hongjoon Choi 1 2,  Moon Suk Kim 2,  Chang-Hee Suh 2,  Wook Kim 3 4,  Sangdun Choi 5 6 7
Affiliations

Affiliations

  • 1 S&K Therapeutics, Suwon, Korea.
  • 2 Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
  • 3 Department of Molecular Science and Technology, Ajou University, Suwon, Korea. wookkim21@ajou.ac.kr.
  • 4 Advanced College of Bio-convergence Engineering, Ajou University, Suwon, Korea. wookkim21@ajou.ac.kr.
  • 5 S&K Therapeutics, Suwon, Korea. sangdunchoi@ajou.ac.kr.
  • 6 Department of Molecular Science and Technology, Ajou University, Suwon, Korea. sangdunchoi@ajou.ac.kr.
  • 7 Advanced College of Bio-convergence Engineering, Ajou University, Suwon, Korea. sangdunchoi@ajou.ac.kr.
  • # Contributed equally.
PMID: 40887497 DOI: 10.1038/s12276-025-01526-w
Abstract

Endosomal Toll-like receptors (TLRs, including TLR3, TLR7, TLR8 and TLR9) play crucial roles in immune responses by recognizing pathogen-associated molecular patterns; however, their aberrant activation is implicated in inflammatory and autoimmune diseases. Developing endosomal TLR inhibitors against autoimmune diseases is clinically essential. Here we synthesized and optimized a series of compounds based on a candidate structure. The lead compounds, ETI41 and ETI60, potently inhibited endosomal TLR-mediated pro-inflammatory signaling with nanomolar activity in cellular, biophysical and in vivo assays. Both ETI41 and ETI60 selectively inhibited endosomal TLRs without affecting surface TLRs, as confirmed by immunoblotting and biophysical analyses. RNA Sequencing revealed that these inhibitors modulated the expression of genes associated with inflammation. In vivo studies have shown that oral administration of ETI41 or ETI60 effectively ameliorates symptoms in mouse models of psoriasis, and systemic lupus erythematosus. These findings indicate that ETI41 and ETI60 hold significant potential as therapeutic agents for the treatment of autoimmune and inflammatory diseases through selective targeting of endosomal TLRs.

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