AbstractMYST proteins (e.g. KAT6A, KAT6B, KAT7) are histone acetyltransferases that epigenetically regulate chromatin accessibility. KAT6 expression is associated with cancer growth and KAT6A is recurrently amplified in several cancer types, including breast and lung. KAT6A complexes with multiple proteins, such as bromodomain and PHD finger containing 1 (BRPF1), enhancing its regulation of cell cycle, estrogenic, and other oncogenic genes. Recent first-in-human clinical data with a dual KAT6A/B inhibitor demonstrated promising efficacy in heavily pre-treated patients with ER+/HER2- breast cancer and provided insight into on-target safety considerations like neutropenia. Reports describing the role of KAT proteins in hematopoietic cells, and non-catalytic functions for KAT6A, led us to hypothesize that a targeted protein degradation approach to selectively degrade KAT6A may improve the anti-cancer activity and safety profile for KAT6 therapies. We report the discovery of potent (<1 nM DC50) oral KAT6A degraders with excellent selectivity over KAT6B and KAT7. Degradation occurred via the proteosome and was dependent on target and E3-ligase binding. KAT6A degraders suppressed breast cancer cell proliferation, enriched in ER+/HER2- models expressing KAT6A, and retained activity in endocrine therapy resistant cells. To assess the differential biology of KAT6A degradation, we compared an inhibitor with a degrader. Strikingly, KAT6A degradation had a deeper anti-proliferative effect in breast cancer cell lines compared to the inhibitor. The superior response was reversible by competition with the binder warhead and an E3-inactive degrader displayed limited activity, suggesting that KAT6A degradation drove this effect. Encouragingly, KAT6A degraders also demonstrated superior anti-proliferative activity in multiple lung cancer cell lines. Mechanistically, RNA-seq revealed degraders induced a more profound global effect on gene expression, enriched in estrogenic, cell cycle, DNA replication and repair, and MYC signaling pathways. Consistent with the gene expression changes, KAT6A degraders induced a deeper reduction in estrogen receptor (ERα) expression. Notably, only KAT6A degraders reduced BRPF1 expression, a subunit of the KAT6 complex, suggesting that degradation of KAT6A may destabilize the protein complex. In vivo, we show a KAT6A degrader robustly inhibits tumor growth, while degrading KAT6A and reducing ERα expression, in a breast cancer xenograft. Lastly, we utilized a predictive assay for neutropenia (CFU-GM), where we found KAT6A-selective degraders were inactive, in contrast to KAT6A/B inhibitors. Our first-in-class KAT6A degraders demonstrated proof-of-concept for a differentiated strategy with potential to improve the depth of response and safety profile for a clinically active anti-cancer target.Citation Format:Monisha Sivakumar, Sarah Pawley, Anthony Reichelderfer, Corey Basch, Jimin Park, Jessica Burtell, Chaoyi Xu, Min Wang, Chun Chen, Justin Kurian, Joy Cote, Miles Cowart, Stephanie Rodgers, Amy Crossan, Joseph Rager, Koichi Ito, Sandy Geeganage, SangHyun Lee, Andrew Combs, Peggy Scherle, Andrew Buesking, Jack Carter. Discovery of first-in-class potent and selective oral degraders of KAT6A that demonstrate anti-cancer activity in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1649.