Abstract
Interleukin-2-inducible T cell kinase is expressed by T cells and amplifies T cell receptor-dependent signals. Interleukin-2-inducible T cell kinase deletion or inhibition reduces production of interleukin-4 and interleukin-13, key drivers of atopic dermatitis. Nerve growth factor signals via the receptor tropomyosin-related kinase A and may promote pruritus in atopic dermatitis lesions. Here we describe PF-07245303, a compound which potently inhibits interleukin-2-inducible T cell kinase and tropomyosin-related kinase family kinases capable of inhibiting T cell receptor-mediated cytokine production from CD4 and CD8 T cells and suppressing nerve growth factor-induced human basophil activation. In human skin explants, PF-07245303 demonstrates inhibition of tropomyosin-related kinase A phosphorylation, suppresses cytokine expression from T cell receptor-activated resident T cells and reverses the expression of atopic dermatitis associated genes. Topical application of PF-07245303 reduces proinflammatory and epidermal changes in a dermatitis model using female mice. By inhibiting both pathogenic inflammatory mechanisms, PF-07245303 may have therapeutic value for patients with atopic dermatitis.
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Data availability
Source data has been provided, and all primary data generated for this study will be readily shared with researchers for reproducibility purposes upon request. The diffraction data and coordinates of ITK bound to the PF-07245303 compound have been deposited in the Protein Data Bank (PDB) under the accession code 9NWX. The RNA sequencing data generated has been deposited in the GEO repository under accession code GSE297645. Source data are provided with this paper.
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Acknowledgements
We thank the staff of the Pfizer Flow Cytometry and Next-Generation Sequencing Technology Centers for their support. We thank Alexia Scaros and Ying Zhang for outsourcing support. We thank Isac Lee and Samir Lal with assistance with the submission of the RNAseq gene expression data and figure formatting.
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A.L.B., K.F., L.J., J.B., J.H.S., K.K.C., C.A., Y.Z., T.A., R.T.S., W.L., A.R., and J.V. performed biochemical, cell-based, ex vivo skin experiments or in vivo study, analyzed the data, and prepared the methods sections. K.H. performed microscopic analysis of tissue sections from in vivo model. N.L.N., S.L. performed crystallography studies and determined the structures. J.E.D., J.W.S., A.C-G., G.M.C., F.E.L., R.A.D., S.D., R.H., M.P., J.I.T., S.W.B., and B.S.G. designed and synthesized PF-07245303. S.A.J., Y.L. conducted transcriptomics and the corresponding quantitative analysis and data visualization. J.G. and S.A.J. performed statistical analysis. J.L.D., S.J., T.L.F., S.J.S., K.N., M.H., F.V., K.L.L., B.S.G., and M.J.P. were involved in the experimental design and data interpretation. J.L.D., S.W.J., J.B., S.L., S.W.B., B.S.G., and M.J.P. wrote the manuscript with input from all authors.
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J.L.D., K.K.C., L.J., A.B., K.F., J.B., S.J., Y.L., J.H.S., Y.Z. T.A., K.H., C.A., R.T.S., J.G., S.B., A.C-G, G.C., J.D., R.A.D., S.D., T.F., R.W.H., S.L., F.L., N.N., M.P., J.S., J.I.T., S.S., K.N., M.H., F.V., K.L.L., B.S.G., and M.J.P. were employees of Pfizer Inc. at the time this work was performed. W.L., A.R., and J.V. were employees of MedPharm Ltd. at the time this work was performed. The authors declare no other competing interests.
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Duffen, J.L., Crouse, K.K., Ji, L. et al. Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70000-6
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DOI: https://doi.org/10.1038/s41467-026-70000-6
