Abstract 450: Discovery of a highly potent KAT6 Inhibitor for potential treatment of advanced, metastatic and refractory ER+Her2- breast cancers

Abstract Frequent genomic alteration of KAT6A and KAT6B have been found in a variety of cancer types. Histone acetyltransferases (HAT) KAT6A and KAT6B can acetylate lysine residues of histone H3 (including H3K23), leading to a relaxing state of chromatin and active transcription of genes regulating cell cycle, cellular senescence, and tissue development; to name a few, genes encoding ER (estrogen receptor), Myc, and Cyclin D1. Inhibition of these processes exerts an anti-tumor effect in many cancer types. We, Innogate Pharma (Innogate), have discovered a novel and highly potent series of small molecule KAT6 inhibitors with strong in vitro potency and robust in vivo anti-tumor efficacy. Innogate’s KAT6 preclinical candidate compound (PCC) exerts single digit nM IC50 activities against KAT6A/6B enzymes with good selectivity over KAT5, KAT7, KAT8. The molecule also demonstrated anti-proliferation activity at sub-nM IC50 in ZR-75-1 and T47D. We also tested enzyme kinetics and found the molecule have favorable binding profile to KAT6A in a fast-on-slow-off manner. The PCC molecule can be converted to salts with potential advantages in CMC development and showed a favorable solubility profile independent of GI pH variation. In ER+Her2-breast cancer ZR-75-1 xenograft models, the molecule at 0.3 mg/kg /PO/QD for 28 days leads to significant tumor growth inhibition and regression with TGI 129% at the termination day 28. Furthermore, in a fulvestrant resistant, ER+HER2- breast cancer PDX model, the molecule displayed excellent anti-tumor efficacy at 10 mg/kg /PO/QD, with tumors completely disappeared on day 22 and without safety issues observed, while the positive control compound still had palpable tumors on termination day 28 at the same dose. In other preclinical studies, the molecule holds good in vitro ADME properties and PK profiles in mice, rats and beagle dogs, favoring a potential once daily oral dose regime in the future clinical setting. The molecule also exhibited good in vitro safety profile in hERG and well tolerated in rodent study. Collectively, these results provide preclinical evidence that our PCC molecule could be a superior KAT6A/6B inhibitor to treat patients with advanced, metastatic, refractory, fulvestrant-sensitive or-resistant, ER+Her2- breast cancers. Citation Format: Congcong Cai, Shiya Zhu, Linjun Wang, Shu Cai, Hongkun Li, Min Wen, Mingxin Qian, Shifeng Liu, Bin Shi, Hancheng Zhang. Discovery of a highly potent KAT6 Inhibitor for potential treatment of advanced, metastatic and refractory ER+Her2- breast cancers [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 450.