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UR-1505, a New Salicylate, Blocks T Cell Activation through Nuclear Factor of Activated T Cells

Palau Pharma, S.A., Pharmacology & Toxicology, Palau-solità i Plegamans, Barcelona, Spain (J.R., A.F.A., S.B., P.M., M.G., M.M., I.R.); and Department of Pharmacology, Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas, School of Pharmacy, University of Granada, Spain (E.B., M.C., J.G., A.Z.)

2-Hydroxy-4(-2,2,3,3,3-pentafluoropropoxy)-benzoic acid (UR-1505), a new molecule chemically related to salicylic acid, has immunomodulator properties and is currently under clinical development for treatment of atopic dermatitis. The present work describes the immunomodulatory profile of UR-1505. UR-1505 targets T cells, inhibiting their proliferation and cytokine production by blocking nuclear factor of activated T cells (NF-AT) DNA-binding activity. The effects of UR-1505 (100-300 µM) on T cell proliferation seems to be dependent on the stimulus, because UR-1505 inhibited CD3/CD28-induced T-cell proliferation, increased p27^KIP levels, and induced G₁/S cell arrest but, interestingly, did not inhibit the Janus tyrosine kinase/signal transducer and activator of transcription-induced T-cell proliferation. These data suggest that UR-1505 acts by means of a specific mechanism inhibiting T cell activation depending on T cell receptor signaling pathway. Furthermore, the antiproliferative effects of UR-1505 are not a consequence of decreased cell viability. In addition to the inhibition of T-cell proliferation, UR-1505 decreased, in a dose-dependent manner, the production of interleukin (IL)-5 and interferon (IFN)- in activated T cells, and this effect was produced at the transcriptional level. Because T-cell proliferation and cytokine production were regulated through NF-AT, we examined the effect of UR-1505 on this transcription factor. According to its effect on IL-5 and IFN- mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on nuclear factor-B and activator protein-1 activities. The effect of UR-1505 on NF-AT is not attributable to a blockade of nuclear import. In conclusion, UR-1505 is a new immunomodulator agent that specifically inhibits NF-AT activation. Because NF-AT regulates the transcription of most genes involved in lymphocyte activation, its selective inactivation results in both decreased T-cell proliferation and cytokine production.

Address correspondence to: Juan Román, Palau Pharma, S.A., Pharmacology and Toxicology, Polígon Industrial Riera de Caldes, Avinguda Camí Reial, 51-57, 08184 Palau-solità i Plegamans (Barcelona) Spain. E-mail: jroman{at}palaupharma.com