Abstract 1739: Identification of a potent and selective KAT6A/6B inhibitor: HW321005 exhibits strong antitumor activity in KAT6A-high ER+/HER2− breast cancer

KAT6A and its paralog KAT6B are histone lysine acetyltransferases (HATs) that regulate gene transcription via the acetylation of histones. Dysregulation of KAT6 leads to lineage-specific gene expression changes in cancer. Overexpression of KAT6 is associated with poorer clinical outcomes in ER+/HER2− breast cancers. Dysregulation of KAT6 activity, including gene amplification, overexpression, fusion, and mutation, is observed in various cancers, including breast cancer. We have developed potent and selective small molecule inhibitors targeting KAT6A/6B. Our proprietary compound, HW321005, inhibits KAT6A/6B with single-digit nanomolar IC50 values, demonstrating high selectivity over other KAT family members. The efficacy of HW321005 was evaluated in multiple cancer cell lines, including ZR-751 (IC50 = 1.7 nM). Treatment with HW321005 led to a marked downregulation of KAT6A-mediated histone acetylation and estrogen receptor signaling in KAT6A-high ER+ breast cancer models. Consistent with in vitro findings, HW321005 showed significant anti-tumor efficacy and a robust pharmacodynamic response (H3K23Ac, acetylation marker; ERα, estrogen receptor signaling marker) in ZR-751 xenograft model in a dose-dependent manner. HW321005 demonstrates substantial biological potency and high selectivity, with favorable drug-like properties, including desirable in vitro ADME characteristics, excellent in vivo exposure, clearance, and good oral bioavailability across multiple preclinical species. These findings highlight the potential of HW321005 as a novel and highly effective KAT6A/6B inhibitor for the treatment of KAT6A-high ER+ breast cancer. IND-enabling studies for HW321005 are planned for early 2025. Citation Format: Xin Zhao, Qun Li, Qian Wu, Zexin Tong, Yang Zang, Tiejun Bing, Lifei Liu, Xuejun Zhang. Identification of a potent and selective KAT6A/6B inhibitor: HW321005 exhibits strong antitumor activity in KAT6A-high ER+/HER2− breast cancer [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 1739.