JTE-607 dihydrochloride

Product NameJTE-607 dihydrochloride
CAS188791-09-5
MFC25H32Cl3N3O5
MW560.9
EINECS
MOL File188791-09-5.mol

Chemical Properties

storage temp.	-20° (des.)
solubility	Soluble in DMSO (up to 25 mg/ml).
form	solid
color	Off-white to pale yellow
Water Solubility	H2O: 2mg/mL, clear
Stability	Stable for 1 year as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
InChIKey	JUJAUEQJEWIWCQ-FJSYBICCSA-N
SMILES	Clc1c(c(cc(c1O)C(=O)N[C@@H](Cc3ccccc3)C(=O)OCC)Cl)OCCN2CCN(CC2)C.Cl.Cl

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Description

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).1It displayed efficacy in a mouse model of septic shock.2JTE-607 also showed inhibitory activity against acute myelogenous leukemia cell lines.3,4Recently, 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).5,6This 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.

Uses

JTE 607 Dihydrochloride is a cytokine release inhibitor.

Definition

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+).

in vivo

JTE-607 (0.3-10 mg/kg, i.v.) shows dose dependent inhibition of mortality after LPS challenge in C. parvum sensitized mice in accordance with a decrease of plasma TNF-α^[1].

Animal Model:	Male C57BL/6 mice (5 to 6 weeks old) are sensitized by injecting Corynebacterium parvum^[1]
Dosage:	0.3, 1, 3, 10 mg/kg
Administration:	Administered intravenously 10 min before the LPS challenge.
Result:	Showed dose dependent inhibition of the mortality at 0.3 to 10 mg/kg and significant effect at 3 and 10 mg/kg.

IC 50

IL-10; IL-6; IL-8

storage

Desiccate at RT

References

[1] M KAKUTANI. JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice.[J]. Inflammation Research, 1999, 48 8: 461-468. DOI:10.1007/s000110050487
[2] HIROYUKI IWAMURA K W Motohide Sato. 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]. ACS Applied Electronic Materials, 2004: 1256-1263. DOI:10.1124/jpet.104.072421
[3] NAOFUMI UESATO . JTE-607, a multiple cytokine production inhibitor, ameliorates disease in a SCID mouse xenograft acute myeloid leukemia model[J]. Experimental hematology, 2006, 34 10: Pages 1385-1392. DOI:10.1016/j.exphem.2006.05.016
[4] NOBUYUKI TAJIMA. JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells[J]. Cancer Science, 2010, 101 3: 774-781. DOI:10.1111/j.1349-7006.2009.01446.x
[5] JUNYA KAKEGAWA. JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA processing[J]. Biochemical and biophysical research communications, 2019, 518 1: Pages 32-37. DOI:10.1016/j.bbrc.2019.08.004
[6] NATHAN T. ROSS. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma[J]. Nature chemical biology, 2019, 16 1: 50-59. DOI:10.1038/s41589-019-0424-1

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