ZSTK474 is an ATP-competitive pan-class I PI3K inhibitor that exhibits inhibitory activity against PI3Kα (IC₅₀=16nM), PI3Kβ (IC₅₀=44nM), PI3Kδ (IC₅₀=4.6nM), and PI3Kγ (IC₅₀=49nM) subtypes[1-2]. By inhibiting the PI3K/Akt signaling pathway, ZSTK474 downregulates phosphorylated Akt and GSK-3β, thereby inducing tumor cell apoptosis and suppressing inflammatory responses[3-4].
In vitro, treatment of sarcoma cells (RD-ES, A673), alveolar rhabdomyosarcoma cells (SJCRH30), or synovial sarcoma cells (SYO-1, Aska-SS, Yamato-SS) with ZSTK474 (0.0039–1μM) for 6–48 hours significantly inhibited the phosphorylation of PI3K downstream signaling proteins AKT (S473/T308) and ribosomal S6 protein (S235/236), while increasing the expression of cleaved PARP and inducing apoptosis[5]. Pre-treatment of human glioblastoma cells (SF295, U87) with ZSTK474 (0.4–1.2μM) for 48 hours, followed by temozolomide (TMZ; 120–180μM) for an additional 48 hours, significantly suppressed cell proliferation, induced apoptosis, and increased DNA double-strand break damage[6].
In vivo, daily oral administration of ZSTK474 (25–100mg/kg) for 14 days in BALB/C nude mice bearing subcutaneous Wilms tumor WiT49 cell xenografts. ZSTK474 significantly inhibited tumor growth and reduced tumor volume and weight[7]. Intravenous administration of ZSTK474 (2mg/kg/day) in combination with oncolytic vesicular stomatitis virus (VSV△51; 2.5×10⁷pfu/kg/day) in BALB/c-nu/nu mice bearing 143B osteosarcoma cell xenografts. ZSTK474 significantly suppressed subcutaneous tumor growth and reduced tumor volume and weight after six treatments[8].
References:
[1] Kong DX, Yamori T. ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system. Acta Pharmacol Sin. 2010 Sep;31(9):1189-97. doi: 10.1038/aps.2010.150.
[2] Kong D, Yamori T. ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. Cancer Sci. 2007 Oct;98(10):1638-42.
[3] Dan S, Okamura M, Mukai Y, et al. ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo. Eur J Cancer. 2012 Apr;48(6):936-43.
[4] Yaguchi S, Fukui Y, Koshimizu I, et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst. 2006 Apr 19;98(8):545-56.
[5] Namatame N, Tamaki N, Yoshizawa Y, et al. Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. Oncotarget. 2018 Oct 12;9(80):35141-35161.
[6] Jiao W, Zhu S, Shao J, et al. ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair. Biomed Res Int. 2022 Jul 13;2022:8568528.
[7] Li M, Liu J, Jin L, et al. ZSTK474 targeting PIK3R3 inhibits the Wilms' tumor through G0 / G1 phase arrest. PLoS One. 2024 Oct 28;19(10):e0312178.
[8] Jiang J, Wang W, Xiang W, et al. The phosphoinositide 3-kinase inhibitor ZSTK474 increases the susceptibility of osteosarcoma cells to oncolytic vesicular stomatitis virus VSVΔ51 via aggravating endoplasmic reticulum stress. Bioengineered. 2021 Dec;12(2):11847-11857.
ZSTK474是一种ATP竞争性的泛I类PI3K抑制剂，对PI3Kα（IC50=16nM）、PI3Kβ（IC50=44nM）、PI3Kδ（IC50=4.6nM）和PI3Kγ（IC50=49nM）亚型均有抑制活性[1-2]。ZSTK474通过抑制PI3K/Akt信号通路，下调磷酸化Akt、GSK-3β等下游蛋白表达，从而发挥诱导肿瘤细胞发生和抑制炎症反应的功能[3-4]。
在体外，ZSTK474（0.0039–1μM）处理肉瘤细胞（RD-ES、A673）、肺泡横纹肌肉瘤细胞（SJCRH30）或滑膜肉瘤细胞（SYO-1、Aska-SS、Yamato-SS）6–48小时。ZSTK474显著抑制PI3K下游信号通路蛋白AKT（S473/T308）和核糖体S6蛋白（S235/236）的磷酸化，并诱导c-PARP表达升高及细胞凋亡[5]。ZSTK474（0.4–1.2μM）预处理人胶质母细胞瘤细胞（SF295、U87）48小时，随后以Temozolomide（TMZ；120–180μM）处理48小时，显著抑制细胞增殖并诱导细胞凋亡，同时增加DNA双链断裂损伤[6]。
在体内，ZSTK474（25–100mg/kg）每日一次口服给药，用于处理携带皮下肾母细胞瘤WiT49细胞异种移植瘤的BALB/C裸鼠14天。ZSTK474显著抑制了皮下肾母细胞瘤的生长并降低肿瘤体积和重量[7]。ZSTK474（2mg/kg/d）联合溶瘤性囊泡性口炎病毒（VSV△51；2.5×10⁷pfu/kg/d）静脉注射，用于处理携带143B骨肉瘤细胞异种移植瘤的BALB/c-nu/nu小鼠6次，显著抑制了皮下肿瘤的生长并降低肿瘤体积和重量[8]。