Shinozuka Tsuyoshi, Ito Shuichiro, Kimura Takako, Izumi Masanori, Wakabayashi Kenji
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
ACS Med Chem Lett. 2021 Apr 21;12(5):817-821. doi: 10.1021/acsmedchemlett.1c00100. eCollection 2021 May 13.
A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure-activity relationship study of high-throughput screening hits and led to the discovery of benzimidazole (DS20362725) and acetophenone analogue (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate and the key interaction between the protein and ligand. Since both analogues avoided PPARγ transcriptional activity, they can be useful tool compounds for investigating biological ERRα functions.
已发现一类新型的雌激素相关受体α（ERRα）激动剂。对高通量筛选所得命中化合物进行的构效关系研究，促成了苯并咪唑（DS20362725）和苯乙酮类似物（DS45500853）的发现。ERRα配体结合域与[未提及具体化合物]和PGC-1α共激活肽形成复合物的X射线晶体结构揭示了配体结合口袋中的构象变化以容纳[未提及具体化合物]，以及蛋白质与配体之间的关键相互作用。由于这两种类似物均避免了PPARγ转录活性，它们可作为研究ERRα生物学功能的有用工具化合物。
