6S57
Crystal structure of human ATAD2 bromodomain in complex withN-(3-(azepan-1-ylsulfonyl)-4-methylphenyl)-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetamide
Summary for 6S57
| Entry DOI | 10.2210/pdb6s57/pdb |
| Descriptor | ATPase family AAA domain-containing protein 2, 1,2-ETHANEDIOL, ~{N}-[3-(azepan-1-ylsulfonyl)-4-methyl-phenyl]-2-[4,4-dimethyl-2,5-bis(oxidanylidene)imidazolidin-1-yl]ethanamide, ... (5 entities in total) |
| Functional Keywords | inhibitor, atad2, bromodomain, epigenetics, atpase family aaa domain-containing protein 2, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 16144.23 |
| Authors | Chung, C. (deposition date: 2019-06-30, release date: 2019-08-21, Last modification date: 2024-05-15) |
| Primary citation | Bamborough, P.,Chung, C.W.,Demont, E.H.,Bridges, A.M.,Craggs, P.D.,Dixon, D.P.,Francis, P.,Furze, R.C.,Grandi, P.,Jones, E.J.,Karamshi, B.,Locke, K.,Lucas, S.C.C.,Michon, A.M.,Mitchell, D.J.,Pogany, P.,Prinjha, R.K.,Rau, C.,Roa, A.M.,Roberts, A.D.,Sheppard, R.J.,Watson, R.J. A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification. J.Med.Chem., 62:7506-7525, 2019 Cited by PubMed Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets. PubMed: 31398032DOI: 10.1021/acs.jmedchem.9b00673 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
Download full validation report
