[A Screening System for the Identification of Fragment Molecules toward the Creation of Nuclear Receptor Ligands].

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, which plays an important role in glucose and lipid metabolism as well as inflammation. The transcriptional activity of PPARγ is regulated by the binding of its ligand and the accompanied conformational change followed by the recruitment of cofactors. The ligand-binding pocket (LBP) of PPARγ comprises multiple sub-pockets and includes a large, Y-shaped cavity. In some cases, more than two ligands simultaneously occupy the LBP and cooperatively activate PPARγ transcription. Inspired by this peculiar character, the author proposed a strategy to create new PPARγ ligands in two steps: first, identifying a combination of ligands that cooperatively activate PPARγ, and second, designing and synthesizing their hybrid structure. Cooperative activation can be detected by a conventional cell-based assay using a reporter gene, which may provide advantages over the existing fragment-based drug discovery approach. Using this strategy, a plant-derived cinnamic acid derivative was found to synergistically activate PPARγ in combination with GW9662, an irreversible antagonist. The designed hybrid structure was synthesized and found to behave as a covalent agonist, which partially activates PPARγ transcription. Structure-activity studies revealed the importance of proximity and orientation in the linkage of the two units. The strategy discussed in this article may contribute to the development of a highly potent PPARγ agonist.