Discovery of DS-9300: a Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor

Abstract

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300 and CBP have attracted attention as drug targets because their aberrant activity or mutations are related to several malignant tumors. We discovered proline derivatives by scaffold hopping-based approach of an initial hit compound 1 having an oxazepane scaffold. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 13 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss. In this paper, we report the process of optimization from hit compound to DS-9300 and the results of pharmacological testing.