Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist

Retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized ROR gamma t inverse agonists to potent ROR gamma t agonists. We succeeded in the identification of potent ROR gamma t agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of ROR gamma t agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing ROR gamma t inverse agonists to agonists.