5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development

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Abstract Objective To investigate the effect of a RORγt inhibitor, 5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine derivative (TTP), on the therapy of lupus nephritis and the safe risk on thymocytes development. Methods BALB/C female mice were 2 months for pristane-induced mice model of lupus nephritis with the treatment of vehicle, prednisone acetate, and TTP. And 4-week-old BALB/C female mice were used for studying the development of thymus with the treatment of vehicle and TTP. Results TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in a pristine induced lupus nephritis mouse model. The treatment of TTP in mice didn’t interfere with thymocyte development, including total thymocyte numbers and proportion of CD4+CD8+ double-positive populations in thymus, and had no substantial effects on thymoma incidence. Surface plasmon resonance identified the TTP had stronger affinity with full length RORγt protein compared the truncated RORγt LBD region, indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed the best binding pocket of TTP to RORγt located in the hinge region of RORγt. Conclusion As a RORγt inhibitor, TTP had potential to develop drug for treating Th17-cell-mediated autoimmune diseases with low safety risk for thymocyte development.

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