NCGC00378430 is a potent inhibitor of the SIX1/EYA2 protein-protein interaction[1]. NCGC00378430 disrupts the SIX1/EYA2 complex, reverses SIX1-induced TGF-β signaling activation, and counteracts the epithelial-mesenchymal transition (EMT) phenotype. NCGC00378430 is applicable in research areas such as breast cancer and pulmonary fibrosis[2-3].
In vitro, NCGC00378430 (10µM) was used to treat KIRC cells for 3 days. NCGC00378430 did not alter cell viability or proliferation, nor did NCGC00378430 impair the binding of SIX1 to the ITGB1 promoter. NCGC00378430 had no effect on SIX1-induced ITGB1 transcription, but did disrupt the SIX1-EYA2 interaction[1]. NCGC00378430 (10–20µM) was applied to MCF7-SIX1, T47D, and MDA-MB-231 breast cancer cell lines for 3 days. NCGC00378430 significantly disrupted the SIX1/EYA2 protein-protein interaction and reversed the TGF-β signaling activation and EMT phenotype induced by SIX1 overexpression[2].
In vivo, NCGC00378430 (25mg/kg) was administered via local injection (near the tumor cell injection site) every other day to NSG mice bearing MCF7-SIX1 tumors, from day 3 to day 21 post-injection. NCGC00378430 significantly inhibited breast cancer metastasis but did not affect the growth of the primary tumor[2]. NCGC00378430 (20mg/kg) was delivered intranasally every three days to either Six1 conditionally overexpressing mice (from day 3 to day 21) or wild-type C57BL/6 mice (from day 10 to day 21) in a bleomycin-induced pulmonary fibrosis model. NCGC00378430 alleviated fibrotic changes and enhanced lung function[3].
References:
[1] Huang S, Hu J, Hu M, et al. Cooperation between SIX1 and DHX9 transcriptionally regulates integrin-focal adhesion signaling mediated metastasis and sunitinib resistance in KIRC. Oncogene. 2024 Sep;43(39):2951-2969.
[2] Zhou H, Blevins MA, Hsu JY, et al. Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis. Cancer Res. 2020 Jun 15;80(12):2689-2702.
[3] Fan Y, Tian Z, Zheng H, et al. Six1 promotes alveolar epithelium senescence in pulmonary fibrosis through regulating Tp53. Int Immunopharmacol. 2025 Dec 3;166:115554.
NCGC00378430是一种有效的SIX1/EYA2相互作用抑制剂[1]。NCGC00378430可破坏SIX1/EYA2复合物、逆转SIX1诱导的TGF-β信号传导和上皮-间质转化（EMT）。NCGC00378430可用于乳腺癌和肺纤维化的相关研究[2-3]。
在体外，NCGC00378430（10μM）处理KIRC细胞3天。NCGC00378430不改变细胞活力与增殖，不阻碍SIX1与ITGB1启动子结合，对SIX1诱导的ITGB1转录无影响，但破坏SIX1-EYA2相互作用[1]。NCGC00378430（10–20μM）处理MCF7-SIX1、T47D及MDA-MB-231乳腺癌细胞3天。NCGC00378430显著破坏SIX1/EYA2蛋白相互作用，逆转SIX1过表达诱导的TGF-β信号通路激活与上皮-间质转化（EMT）表型[2]。
在体内，NCGC00378430（25mg/kg）隔天一次局部注射（于肿瘤细胞注射部位附近），用于处理携带MCF7-SIX1肿瘤的NSG小鼠，从注射后第3天持续至第21天。NCGC00378430显著抑制了乳腺癌的转移，但不影响原发肿瘤的生长[2]。NCGC00378430（20mg/kg）每三天一次滴鼻给药，用于处理博来霉素诱导的肺纤维化模型中的Six1条件性过表达小鼠（从第3天到第21天）或野生型C57BL/6小鼠（从第10天到第21天）。NCGC00378430减轻了纤维化改变并改善了肺功能[3]。