PF-9363 is a potent, selective, orally bioavailable KAT6A/B inhibitor with Ki values of 0.27nM and 2.4nM, respectively [1]. PF-9363 targets KAT6A/B to cause the overall loss of H3K27ac and leads to the transcriptional downregulation of genes involved in the estrogen signaling pathway, cell cycle, E2F pathway, MYC signaling pathway, and epithelial-mesenchymal transition[2]. PF-9363 has been widely used to inhibit the growth of estrogen receptor positive (ER+) breast cancer cells and to prevent tumor progression in xenograft models[3].
In vitro, PF-9363 treatment (20μM) for 14 days significantly inhibited the growth of MOLM-13 cells and reduced the abundance of H3K23ac[4]. PF-9363 (1 μM) was applied to mouse ovarian tissues for 4 days, which significantly inhibited the activation of primordial follicles, reduced the number of primordial follicles, decreased the activity of the mTOR signaling pathway, and led to an increase in the accumulation of FOXO3a in the cell nucleus[5].
In vivo, PF-9363 treatment via daily intragastric administration at a dose of 5mg/kg for 28 days significantly inhibited the tumor volume in the neuroblastoma xenograft model of NSG mice[6]. Oral administration 1mg/kg of PF-9363 every day for 3 weeks significantly inhibited the growth of Phf6 mutant-driven leukemia cells in mice, and prolonged the survival time of mice that received transplanted Phf6R274X leukemia cells[7].
References:
[1] Sharma S, Chung C Y, Uryu S, et al. Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer[J]. Cell Chemical Biology, 2023, 30(10): 1191-1210. e20.
[2] Jeselsohn R, Polyak K. HATS off to KAT6A/B inhibitors: A new way to target estrogen-receptor-positive breast cancer[J]. Cell Chemical Biology, 2023, 30(10): 1183-1185.
[3] Sharma S, Chung J, Uryu S, et al. First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation[J]. Cancer Res, 2021, 81(13_Supplement): 1130.
[4] Bishop T R, Subramanian C, Bilotta E M, et al. Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition[J]. Nature chemical biology, 2023, 19(10): 1215-1222.
[5] Zhang Y, Nie X, Yang L, et al. The role of KAT6A in regulating primordial follicle activation in mouse ovary[J]. American Journal of Physiology-Cell Physiology, 2025, 329(1): C38-C49.
[6] Zimmerman M, Durbin A, Abraham B, et al. Abstract A020: Treatment of neuroblastoma with retinoic acid plus a KAT6A/B inhibitor induces sustained growth arrest and increases GD2 expression as a target for immunotherapy[J]. Cancer Research, 2025, 85(5_Supplement): A020-A020.
[7] Guo Y, Sui P, Yang H, et al. Phf6 truncating mutation drives leukemogenesis via disrupted epigenetic regulation in mice[J]. Leukemia, 2026: 1-15.
PF-9363是一种强效、选择性、口服生物利用度高的KAT6A/B抑制剂，对KAT6A和KAT6B的Ki值分别为0.27nM和2.4nM[1]。PF-9363通过靶向KAT6A/B引起H3K27ac的整体缺失，并导致参与雌激素信号通路、细胞周期、E2F通路、MYC 信号通路和上皮-间质转化的基因转录下调[2]。PF-9363已被广泛用于抑制雌激素受体阳性乳腺癌细胞的生长，并阻止异种移植模型中的肿瘤进展[3]。
在体外，使用20μM的PF-9363处理MOLM-13细胞14天，显著抑制了细胞生长并降低了H3K23ac的丰度[4]。将1μM的PF-9363应用于小鼠卵巢组织4天，显著抑制了原始卵泡的激活，减少了原始卵泡数量，降低了mTOR信号通路的活性，并导致FOXO3a在细胞核内的积累增加[5]。
在体内，每日灌胃给予5mg/kg剂量的PF-9363，持续28天，显著抑制了NSG小鼠神经母细胞瘤异种移植模型中的肿瘤体积[6]。每日口服1mg/mg的PF-9363，持续3周，显著抑制了小鼠体内Phf6突变驱动的白血病细胞生长，并延长了接受Phf6R274X白血病细胞移植的小鼠的生存时间[7]。