Abstract C029: PF-07248144 – First-in-class potent, selective KAT6i in ER+HER2− breast cancer

Abstract KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and regulate lineage-specific transcriptional programs. KAT6A is amplified/overexpressed in breast cancer and exerts an oncogenic role, thus emerging as a promising therapeutic target. Here, we describe discovery and structure of the first KAT6i to enter the clinic, PF-07248144, a highly potent, selective and orally bioavailable KAT6A/B inhibitor derived from a novel benzisoxazole series. PF-8144 demonstrated dose-dependent anti-tumor activity in ER+HER2- breast cancer in correlation with H3K23Ac inhibition, inducing durable tumor regressions in vivo. PF-8144 anti-tumor activity was observed across a varied spectrum of ER+ breast cancer patient-derived xenograft (PDX) models, including models harboring ESR1 or PIK3CA mutations, and models refractory to endocrine therapy and/or cell cycle inhibitors. Transcriptional and epigenetic profiling studies showed reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with KAT6i response. CRISPR screens were performed to identify regulators of KAT6i response and potential combination partners. PF-8144 combination with endocrine therapy and cell cycle inhibitors showed synergistic anti-tumor activity associated with deeper inhibition of estrogen and cell cycle pathways. In the Ph1 study, PF-07248144 + Fulvestrant demonstrated deep and durable anti-tumor activity with 37.2% ORR and 10.7 months mPFS. Based on the strength of these data, a pivotal Ph3 trial of PF-07248144 + Fulvestrant is planned in HR+HER2- mBC after progression on CDK4/6i + ET. Citation Format: Shikhar Sharma, Paul F. Richardson, Jelena Petrovic, Joan Cao, Xinmeng J. Mu, Chi-Yeh Chung, Sean Uryu, Samantha Greasley, Eric Johnson, Oleg Brodsky, Colin Flaveny, Yong Zhang, Pei-Pei Kung, Scott Sutton, Eric Greenwald, Shinji Yamazaki, Rhys Jones, Karen Maegley, Patrick Bingham, Hieu Lam, Aida Sacaan, Hendrik Falk, Paul A. Stupple, Ylva E. Bozikis, Brendon J. Monahan, Ian P. Street, Thomas A. Paul. PF-07248144 – First-in-class potent, selective KAT6i in ER+HER2− breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C029.