JTE-607 (188791-09-5) inhibits inflammatory cytokine production in human peripheral blood mononuclear cells (PBMC’s) without causing immunosuppression: IC50’s = 11 nM (TNF-α), 5.9 nM (IL-1β), 8.8 nM (IL-6), 7.3 nM (IL-8), and 9.1 nM (IL-10).1?It displayed efficacy in a mouse model of septic shock.2?JTE-607 also showed inhibitory activity against acute myelogenous leukemia cell lines.3,4?Recently, the mechanism of action of JTE-607 (a pro-drug, with the active species being the free acid) has been found to be inhibition of pre-messenger RNA endonuclease Cleavage and Polyadenylation Specificity Factor 3 (CPSF3).5,6?This prevents release of newly synthesized mRNA’s resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. Transcripts down-regulated by JTE-607 were related to DNA damage-based phenotype.
JTE 607 Dihydrochloride is a cytokine release inhibitor.
ChEBI: JTE-607 dihydrochloride is the dihydrochloride salt of JTE-607. It is a cytokine inhibitor which suppresses the production of proinflammatory cytokines such as interleukin (IL-1beta), IL-6, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF-alpha). It acts as a pro-drug which is cleaved by carboxylesterase 1 (CES1) to its active free acid form, which then binds to cleavage and polyadenylation specificity factor 3 (CPSF3). It has a role as an anti-inflammatory agent, an antineoplastic agent, an apoptosis inducer, a prodrug, a cardioprotective agent and a CPSF3 inhibitor. It contains a JTE-607(2+).
References/Citations
1) Kakutani?et al.?(1999),?JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice; Inflamm. Res.,?48?461
2) Iwamura?et al.?(2004),?Comparative study of glucocorticoids, cyclosporine A, and JTE-607 [(-)-Ethyl-N{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride] in a mouse septic shock model; J. Pharmacol. Exp. Ther.,?311?1256
3) Uesato?et al.?(2006),?JTE-607, a multiple cytokine production inhibitor, ameliorates disease in a SCID mouse xenograft acute myeloid leukemia model; Exp. Hematol.,?34?1385
4) Tajima?et al.?(2010),?JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells; Cancer Sci.,?101?774
5) Kakegawa?et al.?(2019), JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA; Biochem. Biophys. Res. Commun.,?518?32
6) Ross?et al.?(2020),?CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma; Nat. Chem. Biol.,?16?50
