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.
WM-1119是一种强效KAT6抑制剂，IC50值为6.3µM，对KAT6A、KAT5和KAT7的KD值分别为0.002µM、2.2µM和0.5µM[1]。WM-1119通过自身3-fluoro-5-(pyridine-2-yl)benzoyl部分实现的独特疏水相互作用，展现出对KAT6的有效抑制效力，该部分除了与保守的Arg660、Ser690、Ser693、Leu686和Ile649接触外，还与Ile647和Gly687结合[2]。WM-1119已被广泛用于增加CDKN2A表达并抑制白血病细胞增殖[3]。
在体外，WM-1119处理1小时显著抑制了IgE刺激的大鼠嗜碱性白血病-2H3（RBL-2H3）细胞释放β-氨基己糖苷酶（β-hex），IC50值为33.57µM[4]。使用10µM的WM-1119处理48小时，显著抑制了HepG2和Huh7细胞的活力，导致Edu阳性细胞数量减少[5]。使用1µM的WM-1119处理7天，显著诱导了MT2细胞的增殖停滞，并伴随S期和G2期细胞数量的显著减少 [6]。
在体内，每日四次腹腔注射50mg/kg剂量的WM-1119，持续14天，显著抑制了C57BL/6小鼠的淋巴瘤生长，并减少了肿瘤负荷和脾脏重量[7]。连续21天每日四次腹腔注射60mg/kg剂量的WM-1119，联合顺铂（每三天腹腔注射一次；5mg/kg），显著抑制了小鼠A2780异种移植瘤的生长，并导致肿瘤组织中核β-连环蛋白水平降低[8]。