Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer. [Display omitted] • Discovery of CTx-648/PF-9363: a potent, selective, orally bioavailable KAT6A/B inhibitor • CTx-648/PF-9363 inhibits H3K23Ac leading to growth suppression in breast cancer models • CTx-648/PF-9363 anti-tumor activity enriches in ER+/luminal & KAT6A high breast cancer • In ER+ breast cancer, CTx-648/PF-9363 represses ER, cell cycle, Myc and stem cell pathways Sharma et al. describe the discovery and chemical optimization of a potent, selective, orally bioavailable inhibitor of KAT6A/B with anti-tumor activity in ER+ breast cancer. [ABSTRACT FROM AUTHOR]