posted on 2021-04-19, 18:41authored byAlex Muthengi, Virangika K. Wimalasena, Hailemichael O. Yosief, Melissa J. Bikowitz, Logan H. Sigua, Tingjian Wang, Deyao Li, Zied Gaieb, Gagan Dhawan, Shuai Liu, Jon Erickson, Rommie E. Amaro, Ernst Schönbrunn, Jun Qi, Wei Zhang
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 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.