SU 5402 is a multi-targeted receptor tyrosine kinase inhibitor that inhibit against vascular endothelial growth factor receptor 2 (VEGF-R2) and fibroblast growth factor receptor 1 (FGF-R1) tyrosine kinase activity with IC50 values of 20 and 30nM, respectively[1]. SU 5402 also acts as a FGF-2 inhibitor with an IC50 value of 9µM and produces concentration-dependent reductions in FGF-2 enhancement of granule neuron survival[2].
In vitro, SU 5402 (10μM) pretreated human breast cancer T47D cells for 20min before 10ng/mL bFGF stimulation effectively blocked the binding of bFGF to its receptor FGFR, thereby inhibiting the activation of downstream signaling pathways induced by bFGF. SU 5402 indirectly affects the activation of the PI3K/Akt and MAPK signaling pathways by selectively inhibiting FGFR, thereby effectively suppressing bFGF induced hypoxia-inducible factor (HIF-1α) expression[3]. SU 5402 (20μM) applied on thyroid cancer FTC133 cells for 4h inhibited the phosphorylation of LDHA and PKM2, which was elevated in all analysed cancer subtypes[4]. SU 5402 (10μM) treatment on murine mesenchymal stem cell line C3H10T1/2 cells cultured in osteoblast medium for 2 weeks with 2,000pg/mL fibroblast growth factor 23 (FGF23) diminished the bone-derived effects of FGF23[5].
In vivo, SU 5402 (3μg; 1μL) injected into the lateral ventricle of ICR mice 1h prior to daily oral gavage of paeoniflorin (40mg/kg) for 7 days prevented the antidepressant effects of paeoniflorin and blocked the neuroinflammatory and neurogenic regulatory effects of paeoniflorin[6]. SU 5402 (25mg/kg/day) administrated into monocrotaline-induced pulmonary hypertension (PH) rat model via daily s.c. injection from day 21 to day 42 reversed established monocrotaline-induced PH in rats, decreased the values of pulmonary artery pressure, right ventricular hypertrophy, and peripheral artery muscularization to the levels observed in vehicle-treated rats[7].
References:
[1] Sun L, Liang C X, Tang F, et al. Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases. J Med Chem. 1999 Dec 16;42(25):5120-30.
[2] Skaper S D, Kee W J, Facci L, et al. The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. J Neurochem. 2000 Oct;75(4):1520-7.
[3] Zhang C C, Yu J X, Li S F, et al. Effect of basic fibroblast growth factor on hypoxia-inducible factor (HIF)-1α expression (Exp) and HIF-1 transcription in breast Cancer cell through PI-3 K Akt signaling. Cytokine. 2025 Mar:187:156859.
[4] Kachel P, Trojanowicz B, Sekulla C, et al. Phosphorylation of pyruvate kinase M2 and lactate dehydrogenase A by fibroblast growth factor receptor 1 in benign and malignant thyroid tissue. BMC Cancer. 2015 Mar 18;15:140.
[5] Li Y, He X, Olauson H, Larsson T E, Lindgren U. FGF23 affects the lineage fate determination of mesenchymal stem cells. Calcif Tissue Int. 2013 Dec;93(6):556-64.
[6] Cheng J, Chen M, Wan H Q, et al. Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation. J Ethnopharmacol. 2021 Jun 28:274:114046.
[7] Izikki M, Guignabert C, Fadel E, et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest. 2009 Mar;119(3):512-23.
SU 5402是一种多靶点受体酪氨酸激酶抑制剂，对血管内皮生长因子受体2（VEGF-R2）和成纤维细胞生长因子受体1（FGF-R1）酪氨酸激酶活性的IC50分别为20nM和30nM[1]。SU 5402还可作为FGF-2抑制剂，IC50为9µM，并呈浓度依赖性降低FGF-2对小脑颗粒神经元的促存活作用[2]。
在体外模型中，SU 5402 (10μM) 预处理人乳腺癌T47D细胞20min后再以10ng/mL bFGF刺激，可有效阻断bFGF与其受体FGFR结合，从而抑制bFGF诱导的下游信号通路激活。 SU 5402通过选择性抑制FGFR间接影响PI3K/Akt和MAPK信号通路的激活，从而有效抑制bFGF诱导的缺氧诱导因子 (HIF-1α) 表达[3]。 SU 5402(20μM)处理甲状腺癌FTC133细胞4h，可抑制在所有癌症亚型中升高的LDHA和PKM2的磷酸化[4]。 SU 5402 (10μM) 处理在含有2000pg/mL成纤维细胞生长因子23 (FGF23)成骨培养基中的小鼠间充质干细胞系C3H10T1/2细胞并培养2周，可减弱FGF23的骨源性效应[5]。
SU 5402 (3μg; 1μL) 在每日口服芍药苷 (40mg/kg) 前1h经侧脑室注射入ICR小鼠，共持续7天，可阻止芍药苷的抗抑郁效应，并阻断其神经炎症和神经发生调节作用[6]。 SU 5402 (25mg/kg/day) 从第21天至第42天通过每日皮下注射给予野百合碱诱导的肺动脉高压 (PH) 大鼠模型，可逆转已建立的野百合碱诱导的PH，使肺动脉压、右心室肥厚和外周动脉肌化降至与对照组相当的水平[7]。