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Updated: Jan 30, 2026
Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist
Tomoya Yukawa1, Yoshi Nara1, Mitsunori Kono1
1Pharmaceutical Research Division , Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome , Fujisawa , Kanagawa 251-8555 , Japan.
Abstract:
Retinoic acid receptor-related orphan receptor γt (RORγt) 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 RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt 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 RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.
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