7KPY
Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)
Summary for 7KPY
| Entry DOI | 10.2210/pdb7kpy/pdb |
| Descriptor | Histone acetyltransferase, 1,2-ETHANEDIOL, 2-[2-(3-chloranyl-4-methoxy-phenyl)ethyl]-~{N}-cyclohexyl-7-(3,5-dimethyl-1,2-oxazol-4-yl)imidazo[1,2-a]pyridin-3-amine, ... (4 entities in total) |
| Functional Keywords | epigenetics, inhibitor, drug development, multi domain proteins, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 28840.00 |
| Authors | Schonbrunn, E.,Bikowitz, M. (deposition date: 2020-11-12, release date: 2021-05-19, Last modification date: 2023-10-18) |
| Primary citation | Muthengi, A.,Wimalasena, V.K.,Yosief, H.O.,Bikowitz, M.J.,Sigua, L.H.,Wang, T.,Li, D.,Gaieb, Z.,Dhawan, G.,Liu, S.,Erickson, J.,Amaro, R.E.,Schonbrunn, E.,Qi, J.,Zhang, W. Development of Dimethylisoxazole-Attached Imidazo[1,2- a ]pyridines as Potent and Selective CBP/P300 Inhibitors. J.Med.Chem., 64:5787-5801, 2021 Cited by PubMed Abstract: The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound , CBP IC 72 nM and bromodomain 4, BRD4 IC 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains. PubMed: 33872011DOI: 10.1021/acs.jmedchem.0c02232 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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