JAK Inhibitor I(Merck 5, Pyridone 6)|cas 457081-03-7|DC Chemicals|Price|Buy

Cas No.:	457081-03-7
Chemical Name:	2-(1,1-Dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinolin-7-one
Synonyms:	Merck 5,Merck5
SMILES:	CC(C)(C)C1=NC2=C(N1)C3=C(C=C(C=C3)F)C4=C2C=CNC4=O
Formula:	C₁₈H₁₆FN₃O
M.Wt:	309.3
Purity:	>98%
Sotrage:	2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO

Description:	Pyridone 6 is a pan-JAK inhibitor, which potently inhibits the JAK kinase family, with IC50s of 1 nM for JAK2 and TYK2, 5 nM for JAK3, and 15 nM for JAK1, while displaying significantly weaker affinities (130 nM to >10 mM) for other protein tyrosine kinases.
Target:	JAK2:1 nM (IC50) Tyk2:1 nM (IC50) JAK3:5 nM (IC50) Murine JAK1:15 nM (IC50) CDK2:3.3 μM (IC50) cAMP-dependent kinase:7.1 μM (IC50) Csk:2.1 μM (IC50) Hck:7.7 μM (IC50) Fyn T:0.5 μM (IC50) p38:11 μM (IC50) MAPK:1.78 μM (IC50) Mek:0.16 μM (IC50) IκB Kinase 2:0.3 μM (IC50) KDR:1.4 μM (IC50) Flt-1:1.52 μM (IC50) Flt-4:0.69 μM (IC50) FGFR:1.48 μM (IC50) FGFR2:0.94 μM (IC50) Tek:24 μM (IC50) PDGFR:1.49 μM (IC50) PKC(α):1.2 μM (IC50)
In Vivo:	Pyridone 6 (P6) delays the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6-nano strongly ameliorates atopic dermatitis (AD) in NC/Nga mice, exerting an effect comparable to that of betamethasone ointment, a commonly used drug, which also tested as a positive control. In contrast, empty polylactic acid with glycolic acid (PLGA) nanoparticles (C-nano) seemed to have no effect[2].
In Vitro:	Pyridone 6 is tested as an inhibitor of 21 other protein kinases; Pyridone 6 inhibits these kinases with IC50s ranging from 130 nM to >10 μM. Pyridone 6 inhibits IL2 driven proliferation of CTLL cells with IC50=0.1 μM and IL4 driven proliferation with IC50=0.052 μM[1]. Pyridone 6 (P6) is shown to inhibit kinase by interacting within the ATP-binding cleft of each JAK. The IC50 of Pyridone 6 is 3 nM for all of these cytokines; this is comparable to the reported IC50s of Pyridone 6 for JAK2, Tyk2, and JAK3. Pyridone 6 strongly inhibits Th2 and modestly inhibits Th1, whereas it enhances Th17 development when present within a certain range of concentrations. Pyridone 6 reduces IFN-γ and IL-13, whereas it enhances IL-17 and IL-22 expression. Pyridone 6 also inhibits both Th1 and Th2 development, whereas it promotes Th17 differentiation from naive T cells when present within a certain range of concentrations[2].
Cell Assay:	Naive CD4+ T cells are treated with various concentrations of Pyridone 6 (10 and 30 nM) in RPMI 1640 medium 1 h before the appropriate cytokines are added to create each Th-differentiating condition. Immunoblotting is performed using antiphospho-STAT protein Abs or anti-total STAT protein Abs[2].
Animal Administration:	Mice[2] NC/Nga mice are used at the age of 10-15 wk. To assess the effect of Pyridone 6 treatment on AD symptoms, nanoparticles containing Pyridone 6 (2 mg/body) or empty nanoparticles as a negative control (C-nano) are dissolved in 0.1 mL saline and administered s.c. 1 d after Dfb ointment application; this treatment is repeated twice a week. To assess the effects of recombinant murine IL-17 and IL-22, these cytokines (50 μg/kg) or 100 μL PBS is administered for the same duration as the nanoparticles. Twenty milligrams of 0.064% betamethasone ointment are applied to the dorsal lesion of mice once a week[2].
References:	[1]. Thompson JE, et al. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23. [2]. Nakagawa R, et al. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011 Nov 1;187(9):4611-20.

Cat. No.	Product name	Field of application
DC72649	Nimucitinib	Nimucitinib is a Janus kinase (JAK) inhibitor.
DC70265	BMS-986202	BMS-986202 (BMS 986202) is potent, selective Tyk2 inhibitor that binds to Tyk2 JH2 domain with IC50 of 0.19 nM, Ki of 0.02 nM, >10,000-fold over 273 kinases and pseudokinases; BMS-986202 demonstrated cellular activity (IL-23 IC50=12 nM) in IL-23 stimulated reporter assay (in Kit225 T cells). BMS-986202 also binds Jak1 JH2 with an IC50 of 7.8 nM, but this enzymatic binding did not lead to any functional activities, as BMS-986202 displayed an activity (IC50) of greater than 12.5 μM in the IL-2 stimulated Jak1/3-dependent cellular assay. BMS-986202 showed in vivo efficacy in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus.
DC7667	ZM 39923 hydrochloride	ZM 39923 is an inhibitor of JAK3 (IC50 = 79 nM) that less potently inhibits epidermal growth factor receptor, JAK1, and cyclin-dependent kinase 4 (IC50s = 2.4, 40, and 10 µM, respectively).
DC5022	XL019	XL019 is an orally bioavailable inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity.
DC8080	WHI-P258	WHI-P258 is a negative control for JAK3 inhibitors.
DC7581	WHI-P154	WHI-P154 is a potent JAK3 inhibitor with IC50 of 1.8 μM, no activity against JAK1 or JAK2, also inhibits EGFR, Src, Abl, VEGFR and MAPK, prevents Stat3, but not Stat5 phosphorylation.
DC10431	Upadacitinib	Upadacitinib (ABT-494) is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders with an IC50 of 43 nM.
DC5165	Tofacitinib (CP-690550) Citrate	Tofacitinib is a novel inhibitor of JAK3 with IC50 of 1 nM, 20- to 100-fold less potent versus JAK2 and JAK1. Phase 3.
DC8736	Tofacitinib	Tofacitinib is a novel inhibitor of JAK3 with IC50 of 1 nM, 20- to 100-fold less potent versus JAK2 and JAK1. Phase 3.
DC7318	TG101348(Fedratinib)	TG-101348 (SAR302503) is a selective inhibitor of JAK2 with IC50 of 3 nM, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3, TG-101348 also inhibit BRD4 with IC50 of 340 nM.