WM-1119, a potent KAT6 inhibitor with an IC50 value of 6.3µM, has KD values of 0.002µM, 2.2µM, and 0.5µM for KAT6A, KAT5, and KAT7, respectively [1]. WM-1119 demonstrates effective inhibitory potency for KAT6 through unique hydrophobic interactions enabled by the 3-fluoro-5-(pyridine-2-yl)benzoyl moiety, which engages Ile647 and Gly687 in addition to the conserved contacts with Arg660, Ser690, Ser693, Leu686, and Ile649[2]. WM-1119 has been widely used to increase CDKN2A expression and inhibit leukemic cell proliferation[3].
In vitro, WM-1119 treatment for 1 hour significantly inhibited IgE-stimulated β-hexosaminidase (β-hex) release from rat basophilic leukemia-2H3 (RBL-2H3) cells with an IC50 value of 33.57μM[4]. Treatment with 10µM WM-1119 for 48h significantly inhibited the viability of HepG2 and Huh7 cells, resulting in a decrease in the number of Edu-positive cells[5]. Treatment with WM-1119 at 1µM for 7 days significantly induced proliferation arrest of MT2 cells accompanied by a significant reduction in the number of cells in S and G2 phases[6].
In vivo, Intraperitoneal injection of WM-1119 at a dose of 50mg/kg four times daily for 14 days significantly inhibited lymphoma growth and reduced tumor burden and spleen weight in C57BL/6 mice[7]. For 21 consecutive days, 60mg/kg of WM-1119 was administered intraperitoneally four times a day, in combination with cisplatin (administered intraperitoneally once every three days; 5mg/kg), which significantly inhibited tumor growth in A2780 xenografts in mice and led to a reduction in nuclear β-catenin levels in tumor tissues[8].
References:
[1] Zheng T, Wang S, Liu W, et al. Targeting KAT6A/B as a new therapeutic strategy for cancer therapy[J]. Journal of Medicinal Chemistry, 2025, 68(2): 1002-1020.
[2] Xi Z, Wang J, Ge X, et al. Dancing with KAT6A: Current advances and therapeutic potential in oncology of KAT6A inhibitors[J]. Bioorganic Chemistry, 2026: 109533.
[3] Ling V Y, Jacquelin S, Straube J, et al. Targeting Control of Cell Cycle Enhances the Activity of Conventional Chemotherapy in Chemotherapy-Resistant Acute Myeloid Leukemia[J]. Blood, 2021, 138: 2241.
[4] Baell J B, Leaver D J, Hermans S J, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth[J]. Nature, 2018, 560(7717): 253-257.
[5] Jin Y, Yang R, Ding J, et al. KAT6A is associated with sorafenib resistance and contributes to progression of hepatocellular carcinoma by targeting YAP[J]. Biochemical and Biophysical Research Communications, 2021, 585: 185-190.
[6] Sheridan M, Maqbool M A, Largeot A, et al. The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency[J]. Journal of hematology & oncology, 2024, 17(1): 91.
[7] Baell J B, Leaver D J, Hermans S J, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth[J]. Nature, 2018, 560(7717): 253-257.
[8] Liu W, Zhan Z, Zhang M, et al. KAT6A, a novel regulator of β-catenin, promotes tumorigenicity and chemoresistance in ovarian cancer by acetylating COP1[J]. Theranostics, 2021, 11(13): 6278.