| CAS |
No.215543-92-3 |
| 英文名称 |
SU-5402 |
| 分子式 |
C17H16N2O3 |
| 分子量 |
296.32 |
| 溶解性 |
Soluble in DMSO |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| SMILES |
CC1=CNC(=C1CCC(=O)O)C=C2C3=CC=CC=C3NC2=O |
| InChIKey |
JNDVEAXZWJIOKB-JYRVWZFOSA-N |
| InChI |
InChI=1S/C17H16N2O3/c1-10-9-18-15(11(10)6-7-16(20)21)8-13-12-4-2-3-5-14(12)19-17(13)22/h2-5，8-9，18H，6-7H2，1H3，(H，19，22)(H，20，21)/b13-8- |
| PubChem CID |
5289418 |
| 靶点 |
VEGFR;FGFR;PDGFR |
| 通路 |
Angiogenesis; Protein Tyrosine Kinase/RTK |
| 背景说明 |
SU 5402是一种有效的多靶点受体酪氨酸激酶抑制剂，作用于 VEGFR2，FGFR1 和 PDGFRβ。 |
| 生物活性 |
SU 5402 is a potent multi-targeted receptor tyrosine kinase inhibitor with IC50 of 20 nM， 30 nM， and 510 nM for VEGFR2， FGFR1， and PDGFRβ， respectively.[1-4] |
| In Vitro |
SU 5402 与 FGF-R1 (flg-1) 的催化结构域共结晶，并被发现可抑制 NIH 3T3 细胞中 VEGF-R2 (Flk-1/KDR) 和 PDGF-R 的酪氨酸磷酸化，IC50 值分别为 0.4 和 60.9 μM[1]。为了研究 PKM2 和 LDHA 的磷酸化是否以 FGFR1 特异性方式介导，用受体酪氨酸激酶抑制剂 Dovitinib 和 SU 5402 (SU-5402) 处理 FTC-133。PKM2 和 LDHA 孵育 4 小时后，浓度为 100 nM 的 Dovitinib 处理导致磷酸化状态显著降低。当以 1 nM 和 10 nM 的浓度给药时，未见明显变化。施用 SU 5402 会导致浓度为 20 μM 时 PKM2 和 LDHA 磷酸化的显著降低[2]。 |
| In Vivo |
对 ΔF508-CFTR 纯合子小鼠施用 SU 5402 (SU5402) 抑制 FGFR1 导致部分 ΔF508-CFTR 拯救，如唾液分泌增加所示，这是小鼠的替代“汗液测试”测定。由于唾液分泌通常取决于性别，因此仅选择雄性小鼠进行这些实验。我们的结果表明，用 SU 5402 处理 ΔF508-CFTR 小鼠可将唾液分泌水平恢复到野生型 CFTR 小鼠的约 10%，这表明 SU 5402 对囊性纤维化 (CF) 具有处理作用[3]。选择性 FGFR1 抑制剂 SU 5402 (SU5402) 可预防和/或逆转 MCT (百合碱) 诱导的大鼠 PH。在 MCT 注射后第 21 至 42 天用 SU 5402 处理的大鼠中，第 42 天的评估显示与用载体处理的大鼠相比，肺动脉压 (PAP)、RV/(LV+S) 和远端动脉肌化显著降低 (生理盐水)[4]。 |
| 细胞实验 |
8505C and FTC133 cells are grown in DMEM/F12 suppplemented with 10% FCS and 1% PenStrep and incubated at 37°C， 5% CO2. For B-CPAP RPMI 1640 medium is used. FGFR1 inhibition experiments are performed on FTC133 cells by employment of Receptor Tyrosine Kinase Inhibitors TKI-258 (Dovitinib) and SU 5402 (20μM). Inhibition is conducted over 4 h with the indicated inhibitor concentrations. Control cells receive corresponding concentrations of DMSO[2]. |
| 动物实验 |
Mice[3] Male ΔF508 mice (CFTRtm1Eur on a 129/FVB background) and their wild-type littermates of 9-12 weeks are intraperitoneally injected with DMSO or SU 5402 (dissolved in DMSO at the concentration of 6 mg/mL) at 25 mg/kg body weight， every day for 1 week. The mice are weighed daily and the dosages adjusted accordingly. The mice are then anesthetized by inhaling isoflurane until the end of the procedure. Cholinergic antagonist， Atropine (1 mM， 50 μL) is subcutaneously injected into the right cheek to block potential cholinergic stimulation of the salivary gland. A small strip of filter paper is placed against the injected cheek， for 4 min. Isoprenaline (10 mM， 37.5 μL) is subsequently injected in the same spot to stimulate an adrenergic secretion of saliva (time 0). Filter strips (pre-weighed in an Eppendorf tube) are replaced every 5 min， over a period of 30 min. All six filter strips are weighed at the end of the collection and the results are normalized relative to mg/g body weight. Rats[4] To assess the potential effects of the FGFR1 inhibitor SU 5402 on established PH， adult male Wistar rats (200-250 g) are given MCT (60 mg/kg s.c.)， left untreated for 21 days， then randomly divided into 2 groups (10 animals in each group)， of which one is treated with SU 5402 (25 mg/kg/day) and the other given the vehicle， from day 21 to day 42. All treatments are given once a day by s.c. injection. |
| 数据来源文献 |
[1]. Sun L， 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]. Kachel P， 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.
[3]. Trzcińska-Daneluti AM， et al. RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR. Mol Cell Proteomics. 2015 Jun;14(6):1569-83.
[4]. Izikki M， 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. |
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