Download MendeleyDevelopment of Dimethylisoxazole-Attached Imidazo[1,2- a ]pyridines as Potent and Selective CBP/P300 Inhibitors.
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.(2021) J Med Chem 64: 5787-5801
- PubMed: 33872011
- DOI: https://doi.org/10.1021/acs.jmedchem.0c02232
- Primary Citation of Related Structures:
7KPY - 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- 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 IC 50 72 nM and bromodomain 4, BRD4 IC 50 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.
Organizational Affiliation:
Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, Massachusetts 02125, United States.
