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Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases

2016; Oxford University Press; Volume: 10; Issue: 10 Linguagem: Inglês

10.1093/ecco-jcc/jjw091

1876-4479

Imke Atreya, Alexandra Diall, Radovan Dvorský, Raja Atreya, Christian Henninger, Mathias Grün, Ute Hofmann, Elke Schaeffeler, Rocío López-Posadas, Ilse S. Daehn, Stefanie Zenker, Michael Döbrönti, Clemens Neufert, Ulrike Billmeier, Sebastian Zundler, Gerhard Fritz, Matthias Schwab, Markus F. Neurath,

Inflammatory Bowel Disease

The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD].Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues.Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity.The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.