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

Retinoic-acid-receptor-related orphan nuclear hormone receptor gamma t (ROR gamma t), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, ROR gamma t is essential for thymocyte survival and lymph node development, and ROR gamma t inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of ROR gamma t. In this research, we investigated the effect of ROR gamma t inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4(+)CD8(+) double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length ROR gamma t protein compared with the truncated ROR gamma t LBD region via surface plasmon resonance, which indicated TTP binding to ROR gamma t beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to ROR gamma t is located in the hinge region of ROR gamma t. In summary, as a ROR gamma t inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development.