WP1066 is a reversible competitive inhibitor of STAT3 (Signal Transducer and Activator of Transcription 3), with an IC50 of approximately 2.5µM for the inhibition of STAT3 Tyr705 phosphorylation[1]. WP1066 is commonly used in the research of malignant tumors (such as glioma, hepatocellular carcinoma, and breast cancer) and inflammation-related diseases[2]. WP1066 specifically occupies the SH2 domain pocket of STAT3 through hydrogen bonds and hydrophobic interactions. Its binding can directly block the dimerization process of STAT3[3], thereby inhibiting its nuclear translocation and the transcriptional activation of downstream target genes. This ultimately suppresses tumor cell proliferation, induces tumor cell apoptosis, and reduces the release of inflammatory factors[4].
In vitro, pre-treatment of human oral squamous cell carcinoma Tca8113 and Tca8113/DDP cells with WP1066 (5µM) for 24 hours, followed by treatment with cisplatin (DDP, 0.1–16mg/ml) for 48 hours, significantly inhibits cell proliferation, migration, and invasion capabilities, while reducing STAT3 phosphorylation and miR-21 expression[5]. Treatment of STSW-01 and STSW-01-LUC cells with WP1066 (1.5–3.0µM) for 24 hours significantly decreases STAT3 phosphorylation levels and induces the expression of cell death markers, including necrosis-related protein pMLKL (Ser358) and apoptosis-related protein caspase 3/7[6].
In vivo, WP1066 (40mg/kg) is administered locally, three times per week, to treat a TSCCA xenograft nude mouse model. WP1066 significantly inhibits the increase in tumor volume, reduces tumor cell proliferation and invasion capabilities, and induces tumor cell apoptosis[7]. WP1066 (10–20mg/kg) is administered intraperitoneally, three times per week, to treat gp130757FF mice from 8 weeks of age until 10 weeks of age. WP1066 significantly reduces gastric tumor volume, decreases tumor cell proliferation, and increases tumor cell apoptosis[8].
References:
[1] Horiguchi A, Asano T, Kuroda K, et al. STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br J Cancer. 2010 May 25;102(11):1592-9.
[2] Yang J, Li N, Zhao X, et al. WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin. Biochem Pharmacol. 2024 Mar;221:116040.
[3] Tsurumaki H, Katano H, Sato K, et al. WP1066, a small molecule inhibitor of the JAK/STAT3 pathway, inhibits ceramide glucosyltransferase activity. Biochem Biophys Res Commun. 2017 Sep 16;491(2):265-270.
[4] Tsujita Y, Horiguchi A, Tasaki S, et al. STAT3 inhibition by WP1066 suppresses the growth and invasiveness of bladder cancer cells. Oncol Rep. 2017 Oct;38(4):2197-2204.
[5] Zhou X, Ren Y, Liu A, et al. WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis. Sci Rep. 2014 Dec 17;4:7461.
[6] Allaf A, Victoria B, Rosario R, et al. WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line. Cold Spring Harb Mol Case Stud. 2022 Jun 22;8(4):a006178.
[7] Zhou X, Ren Y, Liu A, et al. STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo. Oncol Rep. 2014 May;31(5):2173-80.
[8] Judd LM, Menheniott TR, Ling H, et al. Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS One. 2014 May 7;9(5):e95993.
WP1066是一种STAT3（信号转导和转录激活因子3）可逆的竞争性抑制剂，针对STAT3 Tyr705位点磷酸化的抑制IC50约为2.5μM[1]，通常用于恶性肿瘤及炎症相关疾病的研究[2]。WP1066 通过氢键和疏水相互作用，特异性占据STAT3的SH2结构域口袋，WP1066的结合可直接阻断STAT3的二聚化过程[3]，进而抑制其核转位及下游靶基因的转录激活，最终抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡，并减少炎症因子的释放[4]。
在体外，WP1066（5µM）预处理人口腔鳞癌Tca8113和Tca8113/DDP细胞48h，随后以顺铂（DDP，0.1–16mg/ml）处理48h，WP1066显著抑制细胞增殖、迁移和侵袭能力，同时降低STAT3磷酸化和miR-21的表达[5]。WP1066（1.5–3.0µM）处理STSW-01及STSW-01-LUC细胞24h，显著降低STAT3磷酸化水平，同时诱导细胞死亡标志物的表达，包括坏死相关蛋白pMLKL（Ser358）和凋亡相关蛋白caspase 3/7[6]。
在体内，WP1066（40mg/kg）局部注射，每周三次，用于处理TSCCA异种移植裸鼠模型。WP1066显著抑制了肿瘤体积的增加，减少了肿瘤细胞的增殖和侵袭能力，同时诱导了肿瘤细胞凋亡[7]。WP1066（10–20mg/kg）腹腔注射，每周三次，用于处理8周龄开始直至10周龄的gp130757FF小鼠。WP1066显著减少了胃肿瘤体积，降低了肿瘤细胞的增殖，同时增加了肿瘤细胞的凋亡[8]。