Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis
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.
Authors
- Fabien Vincent (ORCID: https://orcid.org/0000-0002-8782-0225)
- R. Aldrin Denny (ORCID: https://orcid.org/0000-0001-7441-7077)
- Martin Hegen
- J Volmer
- Shenping Liu (ORCID: https://orcid.org/0000-0001-9400-3007)
- Katherine Hammerman
- Jeonifer Garren
- Mihir D. Parikh
- Julia Shin (ORCID: https://orcid.org/0000-0002-5876-3866)
- Michael J. Primiano (ORCID: https://orcid.org/0000-0003-2405-7450)
- John I. Trujillo (ORCID: https://orcid.org/0000-0003-2303-0256)
- Jennifer E. Davoren (ORCID: https://orcid.org/0000-0002-7312-0666)
- Richard Sheldon
- Frank Lovering (ORCID: https://orcid.org/0000-0002-9515-8200)
- Nicole L. Nedoma (ORCID: https://orcid.org/0009-0000-3809-9120)
- Yizheng Li (ORCID: https://orcid.org/0000-0003-0865-3877)
- Kimberly Crouse
- Kristen K. Ford
- Anthony M. Resek (ORCID: https://orcid.org/0009-0005-2659-6716)
- Scott A. Jelinsky (ORCID: https://orcid.org/0000-0002-5114-0236)
- Susan E. Drozda
- Brian S. Gerstenberger (ORCID: https://orcid.org/0000-0002-6553-1975)
- Joseph W. Strohbach (ORCID: https://orcid.org/0009-0006-9633-7733)
- Scott W. Bagley (ORCID: https://orcid.org/0000-0002-7365-7332)
- Robert W. Hicklin
- Stefanus J. Steyn (ORCID: https://orcid.org/0000-0002-0061-5350)
- Gary M. Chinigo (ORCID: https://orcid.org/0009-0009-6130-6808)
- K. Nocka
- Katherine L. Lee (ORCID: https://orcid.org/0000-0003-0155-290X)
- Amy Brault
- Timothy L. Foley (ORCID: https://orcid.org/0000-0002-5987-5253)
- Agustin Casimiro-garcia
- Jennifer Lynn Duffen
- Tatyana Andreyeva
- Lin Ji
- Y Zhao
- Jonathan Brooks
- Wes LaBarge
- Christina Arnold
Institutions
- Pfizer (United States) (US)
- MedPharm (United Kingdom) (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-09
- DOI
- https://doi.org/10.1038/s41467-026-70000-6
- Citations
- 1
- Primary Topic
- Dermatology and Skin Diseases
- Type
- article
- Field-Weighted Citation Impact
- 54.66
Funders
- Pfizer