Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [BrU-Seq]
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and regulate diverse biological processes including transcription, cell-cycle progression, and stem cell development.  KAT6A exerts an oncogenic role in several tumor types including breast cancer where it is amplified in 10-15% of patients. 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 novel 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 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. Overall design: Human breast cancer cell lines were treated with DMSO or 30 nM PF9363 for 4 hr, 8 hr and 24 hr in triplicates, and subjected to BrU-seq analysis