Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis

  • Nat Commun. 2026 Mar 9. doi: 10.1038/s41467-026-70000-6.
Jennifer L Duffen  1 ,  Kimberly K Crouse  2 ,  Lin Ji  2 ,  Amy L Brault  3 ,  Kristen Ford  3 ,  Jonathan Brooks  2 ,  Scott A Jelinsky  2 ,  Yizheng Li  2 ,  Julia H Shin  2 ,  Yajuan Zhao  2 ,  Tatyana Andreyeva  2 ,  Katherine Hammerman  4 ,  Christina Arnold  2 ,  Richard T Sheldon  2 ,  Jeonifer Garren  5 ,  Wes LaBarge  6 ,  Anthony Resek  6 ,  Jon Volmer  6 ,  Scott W Bagley  3 ,  Agustin Casimiro-Garcia  7 ,  Gary M Chinigo  3 ,  Jennifer E Davoren  7 ,  Rajiah Aldrin Denny  7 ,  Susan Drozda  3 ,  Timothy L Foley  3 ,  Robert W Hicklin  3 ,  Shenping Liu  3 ,  Frank E Lovering  7 ,  Nicole L Nedoma  3 ,  Mihir D Parikh  3 ,  Joseph W Strohbach  7 ,  John I Trujillo  3 ,  Stefanus J Steyn  8 ,  Karl Nocka  2 ,  Martin Hegen  2 ,  Fabien Vincent  3 ,  Katherine L Lee  2 ,  Brian S Gerstenberger  9 ,  Michael J Primiano  2
Affiliations
  • 1. Inflammation and Immunology, Pfizer Inc, Cambridge, MA, USA. [email protected].
  • 2. Inflammation and Immunology, Pfizer Inc, Cambridge, MA, USA.
  • 3. Medicine Design, Pfizer Inc, Groton, CT, USA.
  • 4. Drug Safety Research and Development, Pfizer Inc, Cambridge, MA, USA.
  • 5. Data Sciences and Analytics, Pfizer Inc, Cambridge, MA, USA.
  • 6. MedPharm Ltd, Durham, NC, USA.
  • 7. Medicine Design, Pfizer Inc, Cambridge, MA, USA.
  • 8. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Cambridge, MA, USA.
  • 9. Medicine Design, Pfizer Inc, Cambridge, MA, USA. [email protected].
PMID: 41803126 DOI: 10.1038/s41467-026-70000-6
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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