Noha A M Shendy, Melissa Bikowitz, Logan H Sigua, Yang Zhang, Audrey Mercier, Yousef Khashana, Stephanie Nance, Qi Liu, Ian M Delahunty, Sarah Robinson, Vanshita Goel, Matthew G Rees, Melissa A Ronan, Tingjian Wang, Mustafa Kocak, Jennifer A Roth, Yingzhe Wang, Burgess B Freeman, Brent A Orr, Brian J Abraham, Martine F Roussel, Ernst Schonbrunn, Jun Qi, Adam D Durbin
Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types...
April 25, 2024: Nature Communications