Abstract 459: Discovery and proteomic characterization of a novel KAT6A/B inhibitor

Abstract Lysine histone acetyltransferase 6 (KAT6A/B) is a MYST family member of histone acetyltransferases (HATs), known to regulate gene expression by acetylation of both histone and non-histone substrates. KAT6A/B is a promising cancer drug target, specifically in estrogen receptor positive (ER+) breast cancer, but anti-cancer activity in other cancer indications has also been shown, suggesting a potential benefit for wider patient populations. Despite antitumor activity observed in clinical trials, KAT6i inhibitors are also reported to cause several high grade adverse events, including dysgeusia, neutropenia, and anemia, in some cases leading to treatment discontinuation. The efficacy alongside tolerability profiles of KAT6i reflects the need for improved therapeutic window by developing cleaner, more selective drugs; as well as by identification of additional responsive populations. By applying computational and medicinal chemistry approaches we discovered a novel, highly potent inhibitor of KAT6A/B, demonstrating anti-tumor activity using both in-vitro cell viability assays and tumor growth inhibition in xenograft models. We combined drug sensitivity with basal and perturbational proteomics data of cancer cell lines, in order to provide a mechanistic explanation of KAT6A/Bi mode of action. Proteomic analysis of KAT6i sensitive and resistant cell lines highlighted several candidates for KAT6 predictive biomarker and shed light on the proteome-wide effects of KAT6 inhibition. In summary, these results support KAT6i drug development both within and outside ER+ breast cancer, as well as optimization of more selective KAT6 inhibitors to improve tolerability and therapeutic window. Citation Format: Gali Arad, Avital Hay-Koren, Sagie Brodsky, Andrew Morley, Iris Alchanati, Galina Otonin, Yonatan Katzenelenbogen, Barr Tivon, Alon Shtrikman, Dimitri Kovalerchik, Anjana Shenoy, Katharina Lange, Nitzan Simchi, Eran Seger, Kirill Pevzner. Discovery and proteomic characterization of a novel KAT6A/B inhibitor [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 459.