ETI41 is an orally active, selective TLR inhibitor that targets the nucleoside-binding Site I on TLR7 ( IC50 = 0.63 μM) and TLR9 ( IC50 = 0.16 μM), sparing surface TLRs (including TLR1/TLR2, TLR2/TLR6, TLR4 and TLR5). ETI41 potently inhibits endosomal TLR-mediated pro-inflammatory signaling with nanomolar activity in cellular, biophysical and in vivo assays. ETI41 suppresses the expression of inflammation-associated genes and effectively ameliorates symptoms in mouse models of psoriasis, and systemic lupus erythematosus (SLE). ETI41 can be used for autoimmune and inflammatory diseases research [1].
In Vivo, ETI41 (60 mg/kg, p.o., daily from day 2 to day 5) ameliorates psoriasis induced by IMQ in mice[1]. ETI41 (60 mg/kg, p.o., daily from day 2 to day 9) ameliorates psoriasis induced by IL-23 in mice[1]. ETI41 (30 mg/kg, p.o., daily for 39 days) effectively ameliorates symptoms in a mouse model of SLE[1].
In Vitro, ETI41 (0-200 μM, 4-24 h) effectively inhibits TLR agonist (e.g., Imiquimod (IMQ) for TLR7, ODN2395 for TLR9)-induced TNF-α production in mouse macrophages (RAW 264.7) and human B lymphoblasts (Daudi) cell lines in a dose-dependent manner, without inducing cytotoxic effects[1]. ETI41 (24 h) exhibits inhibitory activity against endosomal TLRs with IC50 values ranging from approximately 100 to 1,000 nM, and inhibits TLR3, TLR7 and TLR8 in a concentration-dependent manner (from 31.2 nM to 10 μM)[1]. ETI41 (5-10 μM, 20 min-8 h) inhibits IMQ- or ODN2395-induced phosphorylation of MAPKs (p-ERK, p-JNK and p-p38), nuclear translocation of the NF-κB p65 subunit, Iκ-Bα degradation and IRF7 expression in RAW 264.7 cells[1]. ETI41 (0.2-1 μM, 30 min) significantly inhibits the production of IL-12p40, IFN-β and CD40 in primary Bone Marrow-derived Dendritic Cells (BMDCs) stimulated with ODN2395[1]. ETI41 (10 μM, 2-4 h) attenuates the IMQ-induced upregulation of multiple inflammation-related genes, including IL1-β, CXCL2, IL18RAP, TNF, PDCD1, NLRP3, NFKBIZ, CCL3, CCL4, KDM6B, ZC3H12A, and PTGS2[1].
References:
[1]. Jeong U, et al. Discovery of ETI41 and ETI41: novel selective endosomal Toll-like receptor inhibitors for the treatment of autoimmune diseases. Exp Mol Med. 2025 Sep;57(9):1951-1962.
In Vivo, ETI41 (60 mg/kg, p.o., daily from day 2 to day 5) ameliorates psoriasis induced by IMQ in mice[1]. ETI41 (60 mg/kg, p.o., daily from day 2 to day 9) ameliorates psoriasis induced by IL-23 in mice[1]. ETI41 (30 mg/kg, p.o., daily for 39 days) effectively ameliorates symptoms in a mouse model of SLE[1].
In Vitro, ETI41 (0-200 μM, 4-24 h) effectively inhibits TLR agonist (e.g., Imiquimod (IMQ) for TLR7, ODN2395 for TLR9)-induced TNF-α production in mouse macrophages (RAW 264.7) and human B lymphoblasts (Daudi) cell lines in a dose-dependent manner, without inducing cytotoxic effects[1]. ETI41 (24 h) exhibits inhibitory activity against endosomal TLRs with IC50 values ranging from approximately 100 to 1,000 nM, and inhibits TLR3, TLR7 and TLR8 in a concentration-dependent manner (from 31.2 nM to 10 μM)[1]. ETI41 (5-10 μM, 20 min-8 h) inhibits IMQ- or ODN2395-induced phosphorylation of MAPKs (p-ERK, p-JNK and p-p38), nuclear translocation of the NF-κB p65 subunit, Iκ-Bα degradation and IRF7 expression in RAW 264.7 cells[1]. ETI41 (0.2-1 μM, 30 min) significantly inhibits the production of IL-12p40, IFN-β and CD40 in primary Bone Marrow-derived Dendritic Cells (BMDCs) stimulated with ODN2395[1]. ETI41 (10 μM, 2-4 h) attenuates the IMQ-induced upregulation of multiple inflammation-related genes, including IL1-β, CXCL2, IL18RAP, TNF, PDCD1, NLRP3, NFKBIZ, CCL3, CCL4, KDM6B, ZC3H12A, and PTGS2[1].
References:
[1]. Jeong U, et al. Discovery of ETI41 and ETI41: novel selective endosomal Toll-like receptor inhibitors for the treatment of autoimmune diseases. Exp Mol Med. 2025 Sep;57(9):1951-1962.