PF-3644022

Potent and Selective MK2 inhibitor CAS# 1276121-88-0

PF-3644022

Catalog No. BCC6136----Order now to get a substantial discount!

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Chemical structure

PF-3644022

3D structure

Chemical Properties of PF-3644022

Cas No. 1276121-88-0 SDF Download SDF
PubChem ID 44631903 Appearance Powder
Formula C21H18N4OS M.Wt 374.46
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO
SMILES CC1CNC2=C(C(=O)N1)SC3=C2C4=C(C=C3)N=C(C=C4)C5=CN=C(C=C5)C
Standard InChIKey CMWRPDHVGMHLSZ-GFCCVEGCSA-N
Standard InChI InChI=1S/C21H18N4OS/c1-11-3-4-13(10-22-11)15-6-5-14-16(25-15)7-8-17-18(14)19-20(27-17)21(26)24-12(2)9-23-19/h3-8,10,12,23H,9H2,1-2H3,(H,24,26)/t12-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PF-3644022

DescriptionPotent, ATP-competitive inhibitor of mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) (IC50 = 5.2 nM; Ki = 3 nM). Inhibits tumor necrosis factor α (TNFα) production in U937 monocytic cells and peripheral blood mononuclear cells (PBMCs) (IC50 = 160 nM); exhibits oral efficacy in acute and chronic inflammatory models.

PF-3644022 Dilution Calculator

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PF-3644022 Molarity Calculator

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Preparing Stock Solutions of PF-3644022

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6705 mL 13.3526 mL 26.7051 mL 53.4102 mL 66.7628 mL
5 mM 0.5341 mL 2.6705 mL 5.341 mL 10.682 mL 13.3526 mL
10 mM 0.2671 mL 1.3353 mL 2.6705 mL 5.341 mL 6.6763 mL
50 mM 0.0534 mL 0.2671 mL 0.5341 mL 1.0682 mL 1.3353 mL
100 mM 0.0267 mL 0.1335 mL 0.2671 mL 0.5341 mL 0.6676 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Organizitions Citing Our Products recently

 
 
 

Calcutta University

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Worcester Polytechnic Institute

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Universidade da Beira Interior

The Institute of Cancer Research

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The University of Michigan
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Universite de Paris
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Auckland University
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The University of Tokyo
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Korea University
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Background on PF-3644022

PF-3644022 is a potent and selective mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) inhibitor (Ki =3 nM). [1]

PF-3644022 is the first oral MK2 inhibitor in both acute and chronic models of inflammation. PF-3644022 reversibly ATP-competitive inhibits MK2 enzyme activity with good selectivity across 200 human kinases. [1]

In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNF production with IC50 value of 160 nM. In LPS-stimulated human whole blood, PF-3644022 blocks TNF and IL-6 production with IC50 values of 1.6 and 10.3 μM, respectively. In U937 cells and blood, Inhibition of TNF correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. [1]

In the rat LPS-induced TNF model, PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a Cmin higher than the EC50 measured. PF-3644022 exhibits efficaciously oral activity and good pharmacokinetic parameters in both the chronic streptococcal cell wall-induced arthritis model and the rat acute LPS-induced TNF model. [1]

References:
1. Mourey RJ, Burnette BL, Brustkern SJ et al. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther. 2010 Jun;333(3):797-807. doi: 10.1124/jpet.110.166173. Epub 2010 Mar 17.

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References on PF-3644022

Role of MK2 signaling pathway in the chronic compression of cervical spinal cord.[Pubmed:26807183]

Am J Transl Res. 2015 Nov 15;7(11):2355-63. eCollection 2015.

OBJECTIVE: In this study, chronic compression of cervical spinal cord was introduced into twy/twy mice and the role of MK2 signaling pathway was investigated in this disease. METHODS: twy/twy mice aged 6-24 weeks were used and the inflammatory response in the cervical spinal cord was observed. The Institute of Cancer Research (ICR) mice were used as controls. MK2 inhibitor (PF-3644022, 30 mg/kg) was administered intragastrically to twy/twy mice. The motor behavior was firstly observed in these three groups by Catwalk gait analysis. And the cervical spinal cord between C2 and C3 of vertebral segments was analyzed by MRI and Western blot assay. RESULTS: The stride length of paws and interlimb coordination reduced in twy/twy mice. However, at 4 weeks after PF-3644022 treatment, a marked improvement was observed in the motor function. The expressions of inflammation related factors (such as IL-1beta, NF-kappaB, TNF-alpha, MK2 and p-MK2) and apoptosis related proteins (such as cleaved caspase-8 and bax/bcl-2) in the spinal cord of twy/twy mice significantly increased as compared to controls, but 4-week treatment with PF-3644022 markedly reduced the expressions of these factors and apoptotic proteins in the cervical spinal cord. CONCLUSION: MK2 signaling pathway is involved in the chronic compression induced inflammation of the cervical spinal cord. Thus, to inhibit the MK2 pathway may used to improve the outcome and prevent the deterioration of neurological dysfunction.

A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation.[Pubmed:20237073]

J Pharmacol Exp Ther. 2010 Jun;333(3):797-807.

Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (K(i) = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFalpha production with similar activity (IC(50) = 160 nM). PF-3644022 blocks TNFalpha and IL-6 production in LPS-stimulated human whole blood with IC(50) values of 1.6 and 10.3 microM, respectively. Inhibition of TNFalpha in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFalpha model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFalpha production in the acute model and inhibition of paw swelling in the chronic model is observed with ED(50) values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C(min) higher than the EC(50) measured in the rat LPS-induced TNFalpha model.

Description

PF-3644022 is a potent, selective, orally active and ATP-competitive MAPKAPK2 (MK2) inhibitor with an IC50 of 5.2 nM and a Ki of 3 nM. PF-3644022 also inhibits MK3 and p38 regulated/activated kinase (PRAK) with IC50s of 53 nM and 5.0 nM, respectively. PF-3644022 potently inhibits TNFα production and has anti-inflammatory effect.

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