8AQM
Crystal structure of PPARG and NCOR2 with an inverse agonist (compound 6a)
Summary for 8AQM
| Entry DOI | 10.2210/pdb8aqm/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 2, 2-chloranyl-~{N}-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]-5-nitro-benzamide, ... (4 entities in total) |
| Functional Keywords | nuclear hormone receptor transcription factor, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 69817.75 |
| Authors | Friberg, A.,Orsi, D.L.,Pook, E.,Braeuer, N.,Lemke, C.T.,Stellfeld, T.,Puetter, V.,Goldstein, J. (deposition date: 2022-08-12, release date: 2022-11-09, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 36270630DOI: 10.1021/acs.jmedchem.2c01379 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
