8AQN

Crystal structure of PPARG and NCOR2 with BAY-4931, an inverse agonist (compound 6c)

8AQN の概要

• エントリーDOI: 10.2210/pdb8aqn/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 2, 2-chloranyl-~{N}-[2-(4-ethylphenyl)-1,3-benzoxazol-5-yl]-5-nitro-benzamide, ... (6 entities in total)
• 機能のキーワード: nuclear hormone receptor transcription factor, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 70070.07

構造登録者

Friberg, A.,Orsi, D.L.,Pook, E.,Braeuer, N.,Lemke, C.T.,Stellfeld, T.,Puetter, V.,Goldstein, J. (登録日: 2022-08-12, 公開日: 2022-11-09, 最終更新日: 2024-10-23)

主引用文献

Orsi, D.L.,Pook, E.,Brauer, N.,Friberg, A.,Lienau, P.,Lemke, C.T.,Stellfeld, T.,Bruggemeier, U.,Putter, V.,Meyer, H.,Baco, M.,Tang, S.,Cherniack, A.D.,Westlake, L.,Bender, S.A.,Kocak, M.,Strathdee, C.A.,Meyerson, M.,Eis, K.,Goldstein, J.T.
Discovery and Structure-Based Design of Potent Covalent PPAR gamma Inverse-Agonists BAY-4931 and BAY-0069 .
J.Med.Chem., 65:14843-14863, 2022

PubMed Abstract: The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation . Improvements to the potency and efficacy of and compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the biology of PPARγ inverse-agonism.

PubMed: 36270630
DOI: 10.1021/acs.jmedchem.2c01379

実験手法

X-RAY DIFFRACTION (1.9 Å)