Abstract 457: QLS1304, a highly potent and selective KAT6A/B inhibitor treating ER+HER2- breast cancer

Abstract KAT6A and KAT6B, members of the MYST family of lysine acetyltransferases, are implicated in estrogen receptor-positive (ER+) breast cancer. KAT6A amplification occurs in about 10% of these patients, linking to overexpression and poorer outcomes. KAT6B is known to be functionally redundant with KAT6A in regulating levels of H3K23Ac, although its specific role in ER+HER2- breast cancer is not well understood. The simultaneous inhibition of KAT6A and KAT6B may lead to a more profound suppression of histone acetylation. Thus, the development of a dual inhibitor targeting KAT6A and KAT6B has been aggressively pursued, with the goal to offer an effective therapeutic solution for patients with ER+ breast cancer. QLS1304 is a highly potent and selective inhibitor of KAT6A/B (KAT6A Ki: 0.2 nM, KAT6B Ki: 0.4 nM; and >200-fold selectivity over KAT5/KAT7/KAT8). H3K23 acetylation was dose-dependently inhibited in ER+HER2- breast cancer cell lines, while ER expression was only suppressed in KAT6A-high cells. QLS1304 demonstrates strong in vitro and in vivo efficacy in multiple ER+HER2- breast cancer CDX models, either as a single agent or in various combinations with current standard therapies. Notably, QLS1304 has demonstrated efficacy in an ESR1 mutant ER+HER2- PDX model derived from a patient resistant to SoC. QLS1304 also exhibits desirable drug-like properties with an excellent pharmacokinetics profile across different animal species, and preclinical safety assessment also indicates a wide therapeutic window. Collectively, QLS1304 appears to be a promising candidate for the treatment of ER+HER2- breast cancer given its efficacy in both SoC-sensitive and SoC-resistant models. Moving it forward into clinical trials is warranted both as single agent and combining with other therapies. Citation Format: Yuxing Zhang, Chundao Yang, Huijie Guo, Changliang He, Lan Zhang, Ling Li, Mengmeng Zhang, Xuejian Zheng, Ping Chen, Dong Yang, Dongdong Wu, Guqin Shi, Daqing Sun, Wenyuan Qian, Weimei Sun, Weikang Tao. QLS1304, a highly potent and selective KAT6A/B inhibitor treating 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 457.