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.