PF-07245303

PF-07245303 is an ITK/TRK inhibitor that reduces the production of inflammatory factors such as IL-4 and IFNγ, and inhibits the phosphorylation of PLCγ1. It suppresses basophil activation induced by nerve growth factor and inhibits TRKA phosphorylation. Additionally, PF-07245303 decreases oxazolone-induced ear swelling in mouse ear tissue. This compound has applications in research on atopic dermatitis.

TrkA:2.94 nM (Kd)

PF-07245303 tightly binds to recombinant human ITK, TRKA, TRKB, and TRKC proteins with respective Kd values of 0.71 nM, 2.94 nM, 8.73 nM, and 10 nM. Under conditions with 1 mM ATP, PF-07245303 effectively inhibits full-length human ITK protein enzyme activity, exhibiting an IC50 of 5.62 nM. It strongly inhibits ITK-dependent PLCγ1 phosphorylation in anti-CD3/CD28-activated Jurkat T cells with an IC50 of 154 nM and suppresses IL-2 release from activated primary human CD4+ T cells with an IC50 of 38.5 nM. Inhibition of IL-2 release in anti-CD3/CD28/CD2-activated human whole blood T cells is observed with an IC50 of 1350 nM (adjusted to 122 nM after protein binding correction). In activated primary human CD4+ T cells, it suppresses the release of IL-4, IL-13, IFNγ, IL-17A, and IL-10 with IC50 values of 73.5 nM, 348 nM, 73.2 nM, 282 nM, and 114.5 nM, respectively. Over a span of 6-7 days, PF-07245303 inhibits cytokine release from differentiated human Th1, Th2, and Th17 cells, with IC50 values for IFNγ, IL-13, and IL-17A being 35.4 nM, 60.9 nM, and 12.5 nM, respectively. The compound also effectively inhibits IFNγ release from anti-CD3/CD28-activated primary human CD8+ T cells with an IC50 of 18.9 nM and blocks human TRKA, TRKB, and TRKC cytoplasmic domain enzyme activities with average IC50 values of 7.2 nM, 12.0 nM, and 20.7 nM under 1 mM ATP conditions. PF-07245303 inhibits phosphorylation of ligand-induced human TRKA, TRKB, and TRKC in U2OS cells expressing p75, with IC50 values of 72.6 nM, 48.7 nM, and 21.7 nM, respectively. It also suppresses NGF-induced primary human basophil activation with an IC50 of 442 nM (corrected to 39.8 nM after protein binding adjustment). The compound impedes NGF-induced TRKA phosphorylation in IL-4/IL-13 pretreated human skin explants. Lastly, PF-07245303 inhibits anti-CD3/CD28 induced IFNG, IL13, and IL2 mRNA expression in a concentration-dependent manner, almost completely at 10 μM, and significantly hinders IL-2 protein release at 1, 3, and 10 μM.

PF-07245303 (2%; topical administration; once daily) significantly reduces oxazolone-induced ear swelling, disease severity scores, and pro-inflammatory cytokine levels in mouse ear tissue, with inhibition of ear thickness observed at various time points ranging from 43% to 61%.