WHI-P131

• CAT Number: I002558
• CAS Number: 202475-60-3
• Molecular Formula: C₁₆H₁₅N₃O₃
• Molecular Weight: 297.31
• Purity: ≥95%
• Target: JAK
• Solubility: DMSO：≥ 3 mg/mL
• Storage: Store at -20°C
• IC50: 78 uM (JAK3)[1]
• InChI: InChI=1S/C16H15N3O3/c1-21-14-7-12-13(8-15(14)22-2)17-9-18-16(12)19-10-3-5-11(20)6-4-10/h3-9,20H,1-2H3,(H,17,18,19)
• InChIKey: HOZUXBLMYUPGPZ-UHFFFAOYSA-N
• SMILES: COC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=C(C=C3)O)OC

Janex-1 is a cell-permeable, reversible, potent, ATP-competitive, and specific inhibitor of JAK3 (IC50 = 78 μM); has no effect on JAK1, JAK2, or Zap/Syk or SRC tyrosine kinases.IC50 Value: 78 uM (JAK3)[1]Target: JAK3in vitro: WHI-P131, which showed potent JAK3-inhibitory activity (IC50 of 78 microM), did not inhibit JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN, or the receptor family tyrosine kinase insulin receptor kinase, even at concentrations as high as 350 microM. ANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor kappaB (NF-kappaB) and JAK/signal transducer and activator of transcription (STAT) pathways [2]. The antigen-induced degranulation and activation of MAPKs were inhibited by WHI-P131 and WHI-P154 in both groups of BMMCs, indicating that these compounds inhibit a certain step except for Jak3. The antigen-induced increase in the activity of Fyn, a probable tyrosine kinase of Gab2, was also inhibited by WHI-P131 and WHI-P154 in RBL-2H3 cells [3].in vivo: The incidence of diabetes at 25 weeks was only 9% for NOD females treated with daily injections of JANEX-1 (100 mg/kg/day) from Week 10 through Week 25 (P = 0.007). Furthermore, JANEX-1 prevented the development of insulitis and diabetes in NOD-scid/scid females after adoptive transfer of splenocytes from diabetic NOD females [4]. After intraperitoneal (i.p.) administration of two consecutive bolus doses of 25 mg/kg injected 30 min apart at dose level of 25 mg/kg, WHI-P131 was rapidly absorbed with an observed C(max) of 82.6 microM, which is higher than the target concentration of 30 microM, at which WHI-P131 abrogates mast cell responses in vitro and the time to reach the maximum plasma concentration (t(max)) was 10.0+/-2.9 min. At a nontoxic 50 mg/kg dose level, WHI-P131 prevented compound 48/80-induced mast cell histamine release and fatal anaphylaxis in mice [5].Toxicity: N/AClinical trial: N/A

Reference

1:Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor-α-induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice. Lee JE, Lee AS, Kim DH, Jung YJ, Lee S, Park BH, Lee SH, Park SK, Kim W, Kang KP.Int J Mol Med. 2012 May;29(5):864-70. doi: 10.3892/ijmm.2012.920. Epub 2012 Feb 16. PMID: 22344597 2:JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-kappaB activation and the JAK/STAT pathway. Lv N, Kim EK, Song MY, Choi HN, Moon WS, Park SJ, Park JW, Kwon KB, Park BH.Exp Cell Res. 2009 Jul 15;315(12):2064-71. doi: 10.1016/j.yexcr.2009.04.021. Epub 2009 May 3. PMID: 19414010 3:Anti-inflammatory activity profile of JANEX-1 in preclinical animal models. Uckun FM, Tibbles H, Ozer Z, Qazi S, Vassilev A.Bioorg Med Chem. 2008 Feb 1;16(3):1287-98. Epub 2007 Oct 24. PMID: 18024136 4:Targeting mast cells in endometriosis with janus kinase 3 inhibitor, JANEX-1. D/’Cruz OJ, Uckun FM.Am J Reprod Immunol. 2007 Aug;58(2):75-97. Review. PMID: 17631002 5:Prevention of islet allograft rejection in diabetic mice by targeting Janus Kinase 3 with 4-(4/’-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-1). Cetkovic-Cvrlje M, Dragt AL, Uckun FM.Arzneimittelforschung. 2003;53(9):648-54. PMID: 14558439 6:Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. Cetkovic-Cvrlje M, Dragt AL, Vassilev A, Liu XP, Uckun FM.Clin Immunol. 2003 Mar;106(3):213-25. PMID: 12706408 7:Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model. Uckun FM, Roers BA, Waurzyniak B, Liu XP, Cetkovic-Cvrlje M.Blood. 2002 Jun 1;99(11):4192-9. PMID: 12010825 Free Article