JTE-607 | mRNA processing inhibitor

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.

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