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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月9日

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  • Jennifer L. Duffen,
  • Kimberly K. Crouse,
  • Lin Ji,
  • Amy L. Brault,
  • Kristen Ford,
  • Jonathan Brooks,
  • Scott A. Jelinsky,
  • Yizheng Li,
  • Julia H. Shin,
  • Yajuan Zhao,
  • Tatyana Andreyeva,
  • Katherine Hammerman,
  • Christina Arnold,
  • Richard T. Sheldon,
  • Jeonifer Garren,
  • Wes LaBarge,
  • Anthony Resek,
  • Jon Volmer,
  • Scott W. Bagley,
  • Agustin Casimiro-Garcia,
  • Gary M. Chinigo,
  • Jennifer E. Davoren,
  • Rajiah Aldrin Denny,
  • Susan Drozda,
  • Timothy L. Foley,
  • Robert W. Hicklin,
  • Shenping Liu,
  • Frank E. Lovering,
  • Nicole L. Nedoma,
  • Mihir D. Parikh,
  • Joseph W. Strohbach,
  • John I. Trujillo,
  • Stefanus J. Steyn,
  • Karl Nocka,
  • Martin Hegen,
  • Fabien Vincent,
  • Katherine L. Lee,
  • Brian S. Gerstenberger,
  • Michael J. Primiano

摘要

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.