• J Crohns Colitis · Oct 2016

    Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases.

    • Imke Atreya, Alexandra Diall, Radovan Dvorsky, Raja Atreya, Christian Henninger, Mathias Grün, Ute Hofmann, Elke Schaeffeler, Rocío López-Posadas, Ilse Daehn, Stefanie Zenker, Michael Döbrönti, Clemens Neufert, Ulrike Billmeier, Sebastian Zundler, Gerhard Fritz, Matthias Schwab, and Markus F Neurath.
    • Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
    • J Crohns Colitis. 2016 Oct 1; 10 (10): 1132-43.

    Background And AimsThe 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].MethodsRac1 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.ResultsSeveral 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.ConclusionsThe Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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