PF-07245303 is a potent, dual inhibitor of Interleukin-2-inducible T cell kinase (ITK) and tropomyosin-related kinase (TRK) family kinases with IC50 of 5.62 nM (human ITK, 1 mM ATP), inhibits human TRKA, TRKB, and TRKC with IC50 of 7.2 nM, 12.0 nM, and 20.7 nM, respectively.
PF-07245303 inhibits ITK-mediated phosphorylation of PLCγ1 on residue Y783 in stimulated Jurkat T cells stimulated with anti-CD3 and anti-CD28 antibodies with IC50 of 154 nM.
PF-07245303 demonstrates potent inhibition of anti-CD3 and anti-CD28 antibody-mediated stimulation of the T cell derived cytokine IL-2 from isolated human CD4+ T cells with an IC50 value of 38.5 nM.
PF-07245303 inhibits IL-2 production from human blood T cells stimulated in vitro with anti-CD3, anti-CD28 and anti-CD2 antibodies with IC50 of 1350 nM.
PF-07245303 inhibits cytokine production from CD4+ T cells, Th1, Th2, and Th17 differentiated cells, and CD8+ T cells, inhibits the release of IFNγ, IL-13 and IL-17A from stimulated human naïve CD4+ T cells skewed to Th1, Th2 and Th17, respectively, with IC50 values of 35.4 nM for IFNγ release, 60.9 nM for IL-13 release, and 12.5 nM for IL-17A release.
PF-07245303 is also capable of potently inhibiting IFNγ release from TCR-activated human CD8+ T cells with an IC50 of 18.9 nM.
PF-07245303 demonstrates inhibition of TRKA-, TRKB- or TRKC-dependent phosphorylation in the presence of p75 with IC50 values of 72.6 nM, 48.7 nM, and 21.7 nM respectively.
PF-07245303 demonstrates inhibition of NGF-dependent increases in the percent of human blood cells positive for CD203c with IC50 of 442 nM.
PF-07245303 inhibits activation of resident dermal T cells in ex vivo human skin sections stimulated with anti-CD3 and anti-CD28 antibodies.
PF-07245303 reverses the expression of many genes associated with atopic dermatitis in human skin explant model, including CXCL11, IFNG, IL2, IL4, IL13, IL17A, FLG, FLG2, IL31RA, NGF, OSMR and IL4R, reduces ear thickness, ear tissue cytokines, and disease severity in a mouse model of oxazolone-induced dermatitis.
