Structural highlights
Publication Abstract from PubMedThe 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-a]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 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 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. Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors.,Muthengi A, Wimalasena VK, Yosief HO, Bikowitz MJ, Sigua LH, Wang T, Li D, Gaieb Z, Dhawan G, Liu S, Erickson J, Amaro RE, Schonbrunn E, Qi J, Zhang W J Med Chem. 2021 May 13;64(9):5787-5801. doi: 10.1021/acs.jmedchem.0c02232. Epub , 2021 Apr 19. PMID:33872011[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||||
This page was last modified 09:29, 26 May 2021.