Structure-activity relationship-guided development of retinoic acid receptor-related orphan receptor gamma (RORγ)-selective inverse agonists with a phenanthridin-6(5H)-one skeleton from a liver X receptor ligand.
Retinoic acid receptor-related orphan receptors (RORs), which belong to the nuclear receptor superfamily, regulate many physiological processes, including hepatic gluconeogenesis, lipid metabolism, immune function and circadian rhythm. Since RORs resemble liver X receptors (LXRs) in the fold structure of their ligand-binding domains, we speculated that ROR-mediated transcription might be modulated by LXR ligands, in line with the multi-template hypothesis. Therefore, we screened our LXR ligand library for compounds with ROR ligand activity and identified a novel ROR ligand with a phenanthridin-6(5H)-one skeleton. Structure-activity relationship studies aimed at separating ROR inverse agonistic activity from LXR-agonistic activity enabled us to develop a series of ROR inverse agonists based on the phenanthridin-6(5H)-one skeleton, including a RORγ-selective inverse agonist.
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yuko
Y
Nishiyama
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Masahiko
M
Nakamura
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Takashi
T
Misawa
Department of Biology, Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.
Madoka
M
Nakagomi
Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Makoto
M
Makishima
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: m-ishikawa@iam.u-tokyo.ac.jp.
Minoru
M
Ishikawa
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yuichi
Y
Hashimoto
D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000737:chemistry / Q000378:metabolism; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010616:Phenanthrenes; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma; C040601:phenanthridone
Inverse agonist; LXR; Phenanthridinone; ROR