Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases

• Published in: Journal of Crohn's and colitis 2016-10, Vol.10 (10), p.1132-1143
• Main Authors: Atreya, Imke, Diall, Alexandra, Dvorsky, Radovan, Atreya, Raja, Henninger, Christian, Grün, Mathias, Hofmann, Ute, Schaeffeler, Elke, López-Posadas, Rocío, Daehn, Ilse, Zenker, Stefanie, Döbrönti, Michael, Neufert, Clemens, Billmeier, Ulrike, Zundler, Sebastian, Fritz, Gerhard, Schwab, Matthias, Neurath, Markus F.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Biomarkers - metabolism; Case-Control Studies; Designer Drugs - pharmacology; Designer Drugs - therapeutic use; Drug Design; Humans; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Mercaptopurine - analogs & derivatives; Mercaptopurine - pharmacology; Mercaptopurine - therapeutic use; Proto-Oncogene Proteins c-vav - metabolism; rac1 GTP-Binding Protein - metabolism; Signal Transduction - drug effects; T-Lymphocytes - metabolism
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjw091

Background and Aims: 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]. Methods: 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. Results: 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. Conclusions: 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.