Genetic mutations and inhibitors of p300 and CBP.

The p300 and CBP highly homologous acetyltransferases, are linked to malignant transformation and cancer progression. The longstanding attempts to find small molecules to block these enzymes in cancer have led to the identification of two inhibitor classes that target the acetyltransferase catalytic domain (HAT) or acetylated protein recognizing bromodomain (BRD), and related pharmacological agents such as dual BRD/BET inhibitors and PROTAC degraders. Although p300 and CBP behave as a synthetic lethal pair and their inhibition emerged promising in anticancer in vitro and in vivo studies, clinical approval has lagged. In this review we examine mutations in EP300 and CREBBP and describe their frequency and potential impacts. Particular attention is paid to genetic alterations in HAT and bromodomain simultaneously in EP300 and CREBBP, and we discuss how these mutations may influence efficacy of pharmacological agents.