PF-3644022 is a potent, ATP-competitive inhibitor of mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) (IC50 = 5.2 nM and Ki = 3 nM). It inhibits tumor necrosis factor α (TNFα) production in U937 monocytic cells and peripheral blood mononuclear cells (PBMCs) (IC50 = 160 nM) and exhibits oral efficacy in acute and chronic inflammatory models.
Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a critical factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins[3]. PF-3644022 is a potent, selective, orally active and ATP-competitive MK2 inhibitor. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFalpha production with similar activity (IC50 = 160 nM). PF-3644022 blocks TNFalpha and IL-6 production in LPS-stimulated human whole blood with IC50 of 1.6 and 10.3 mM, respectively.[4]. PF-3644022 increases the expression of Arg1 and decreases iNOS. Realtime PCR revealed the increased expressions of inflammation related factors (such as IL-1β, NF-κB, TNF-α, MK2) and pro-apoptotic gene (Bax). The BMS score showed a reduced motor function of the twy/twy mice. The motor function was also enhanced with the treatment of PF-3644022[5].
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