PF-3644022

Cas No.:	1276121-88-0
Chemical Name:	(10R)-9,10,11,12-Tetrahydro-10-methyl-3-(6-methyl-3-pyridinyl)-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one
Synonyms:	PF 3644022;PF3644022
SMILES:	C1CCC([C@H](C(NC2=CC3=C4C(C(=NC4=C2)C2C=NN(C)C=2)=CNNC3=O)=O)N)CC1
Formula:	C21H18N4Os
M.Wt:	374.46
Purity:	>98%
Sotrage:	2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO

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[1].
Target:	IC50: 5.2 nM (MK2), 5.0 nM (PRAK) and 53 nM (MK3)[1]. Ki: 3 nM (MK2)[1]
In Vivo:	PF-3644022 (3-100 mg/kg; oral gavage; twice a day; for 12 days; Lewis rats) treatment shows dose-dependent inhibition of chronic paw swelling measured on day 21 after 12 days of oral dosing, with ED50 value of 20 mg/kg[1]. Animal Model: Female Lewis rats (125-140 g) injected with streptococcal cell wall[1] Dosage: 3 mg/kg, 10 mg/kg, 30 mg/kg, 50 mg/kg, 100 mg/kg Administration: Oral gavage; twice a day; for 12 days Result: Showed dose-dependent inhibition of chronic paw swelling measured on day 21 after 12 days of oral dosing.
In Vitro:	The inhibitory activity of PF-3644022 against other MAPKAP kinase family members is evaluated. Other than MNK2 with an IC50 of 148 nM, other family members are largely not inhibited, showing at least several hundred-fold selectivity versus MK2[1]. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFα production with similar activity (IC50 of 160 nM). PF-3644022 blocks TNFα and IL-6 production in LPS-stimulated human whole blood with IC50 values of 1.6 and 10.3 μM, respectively. Inhibition of TNFα in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity[1].
References:	[1]. Mourey RJ, 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