PD173074
(Synonyms: PD 173074,PD-173074) 目录号 : GC17943
PD173074是一种ATP竞争性FGFR1和VEGFR2抑制剂，IC50值分别为26nM和100-200nM，对FGFR1的选择性高于PDGFR和c-Src。
Cas No.:219580-11-7
Sample solution is provided at 25 µL, 10mM.
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PD173074 is an ATP-competitive FGFR1 and VEGFR2 inhibitor with an IC50 value of 26nM and 100-200nM, respectively, showing higher selectivity for FGFR1 over PDGFR and c-Src[1]. PD173074 weakly inhibits the activities of Src, InsR, EGFR, PDGFR, MEK, and PKC[2].
in vitro, PD173074 (0.5, 1, 10, 20 and 50μM; 48h) blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells[3]. PD173074 (0.25 or 1µmol/L, 20µL/well; 4h)reverses MRP7 (ABCC10)-mediated multidrug resistance[4]. PD173074 (0-100μM; 30min) binds to the C-terminus of oncofetal architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) and modulates its DNA-binding and transcriptional activation functions[5].
in vivo, PD173074 (50mg/kg; up to 28 days; goral gavage) blocks small cell lung cancer growth in a nude mice model[6]. PD173074 (20 mg/kg; 3 days; i.p)block FGFR-dependent urothelial carcinoma growth in a Balb/c mice model[7]. PD173074 (20mg/kg; once per day; 10 days; i.p) improves antitumor immunity and impairs breast cancer metastasis in a Balb/c mice model[8].
References:
[1] Dimitroff, C J et al. “Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy.” *Investigational new drugs* vol. 17,2 (1999): 121-35. doi:10.1023/a:1006367032156
[2] Tan, Li et al. “Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.” *Proceedings of the National Academy of Sciences of the United States of America* vol. 111,45 (2014): E4869-77. doi:10.1073/pnas.1403438111
[3] Qiao, Chuchu et al. “PD173074 blocks G1/S transition via CUL3-mediated ubiquitin protease in HepG2 and Hep3B cells.” *PloS one* vol. 15,6 e0234708. 18 Jun. 2020, doi:10.1371/journal.pone.0234708
[4] Anreddy, Nagaraju et al. “PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.” *Acta pharmaceutica Sinica. B* vol. 4,3 (2014): 202-7. doi:10.1016/j.apsb.2014.02.003
[5] Ahmed, Syed Moiz et al. “The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions.” *FEBS letters* vol. 597,15 (2023): 1977-1988. doi:10.1002/1873-3468.14675
[6] Pardo, Olivier E et al. “The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.” *Cancer research*vol. 69,22 (2009): 8645-51. doi:10.1158/0008-5472.CAN-09-1576
[7] Lamont, F R et al. “Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo.” *British journal of cancer* vol. 104,1 (2011): 75-82. doi:10.1038/sj.bjc.6606016
[8] Ye, Tinghong et al. “Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis.” *Breast cancer research and treatment* vol. 143,3 (2014): 435-46. doi:10.1007/s10549-013-2829-y
PD173074是一种ATP竞争性FGFR1和VEGFR2抑制剂，IC50值分别为26nM和100-200nM，对FGFR1的选择性高于PDGFR和c-Src[1]。PD173074抑制Src、InsR、EGFR、PDGFR、MEK和PKC的活性[2]。
在体外，PD173074(0.5、1、10、20、50μM；48h)通过cul3介导的泛素蛋白酶阻断HepG2和Hep3B细胞的G1/S细胞周期转变[3]。PD173074(0.25或1µmol/L； 20µL/孔；4h)逆转MRP7 （ABCC10）介导的多药耐药[4]。PD173074(0 - 100μM；30min)结合到癌胎染色质因子高迁移率组AT-hook 2 (HMGA2)的c端并调节其DNA结合和转录激活功能[5]。
在体内，PD173074 (50mg/kg；最高28天；口服灌胃)在裸鼠模型中阻断小细胞肺癌生长[6]。PD173074 (20mg/kg；3天；腹腔注射）在Balb/c小鼠模型中阻断FGFR依赖性尿路上皮癌生长[7]。PD173074(20毫克/公斤；每天一次；10天；腹腔注射）在Balb/c小鼠模型中提高抗肿瘤免疫，抑制乳腺癌转移[8]。
| Kinase experiment [1]: | |
Preparation Method | The assay media for TK activity contained 25mM HEPES buffer (pH 7.4), 150mM NaCl, 10mM MnCl2, 0.1mM sodium orthovanadate, 750µg/ml of random co-polymer of glutamic acid and tyrosine (4:1), various concentrations of inhibitor and 60–75ng of enzyme. The reaction (total volume, 100µL) was initiated by the addition of [γ-32P]ATP (50µM ATP containing 0.4µCi [32P]ATP per incubation. Samples were incubated for 10 minutes at 25℃ and terminated by the addition of 30% trichloroacetic acid. |
Reaction Conditions | 10 minutes at 25℃ |
Applications | PD173074 displayed selective inhibitory activity towards FGFR1TK at 26nM. |
| Cell experiment [2]: | |
Cell lines | HepG2, Hep3B, human normal liver cell line HL7702 |
Preparation Method | HepG2, Hep3B or HL7702 cells were seeded into 96-well plate at 5000cells/well. After adherence, the cells were treated with different concentrations of PD173074 (0.5, 1, 10, 20 and 50μM). 48h later, the cells were incubated with MTT solution (500μg/mL) for 4h at 37°C. The formazan was solubilized with DMSO and relative cell viability was measured at 490nm with a microplate reader. Growth inhibition in response to various concentrations of PD173074 was calculated using GraphPad Prism 7.0. |
Reaction Conditions | 0.5, 1, 10, 20 and 50μM; 48h |
Applications | PD173074 significantly arrested HepG2 and Hep3B cells in G1 phase and inhibited cell proliferation. |
| Animal experiment [3]: | |
Animal models | nude mice |
Preparation Method | H510 (1:1 cell suspension) or H69 cells were implanted into the flank of nude mice. When tumors became measurable, 50mg/kg PD173074/mice or equivalent volume of buffer alone were administered daily for 14 or 28d. In addition, mice received or did not receive two doses of 5mg/kg cisplatin. Tumor volume was monitored using a calliper. Animals were sacrificed when tumor burden reached 15mm in any dimension and survival recorded as a Kaplan-Meier plot. Tissues were formalin fixed and paraffin embedded before staining as indicated in the figure legends. For the endomucin experiments, pictures were acquired using a ×10 objective and analyzed using ImageJ. For activated Caspase 3 and cytokeratin 18 scoring, the number of positive cells in five high-power field views/tumor (five tumors per condition) was determined and results represented as bar graphs. The total number of nuclei per field was determined by manual counting using event flagging in Metamorph. |
Dosage form | 50mg/kg;up to 28 days; goral gavage |
Applications | In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham–treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. In H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. |
References: | |
| Cas No. | 219580-11-7 | SDF | |
| 别名 | PD 173074,PD-173074 | ||
| 化学名 | 1-tert-butyl-3-[2-[4-(diethylamino)butylamino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]urea | ||
| Canonical SMILES | CCN(CC)CCCCNC1=NC2=NC(=C(C=C2C=N1)C3=CC(=CC(=C3)OC)OC)NC(=O)NC(C)(C)C | ||
| 分子式 | C28H41N7O3 | 分子量 | 523.67 |
| 溶解度 | ≥ 26.1835mg/mL in DMSO, ≥ 108.4 mg/mL in EtOH with ultrasonic | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9096 mL | 9.548 mL | 19.096 mL |
| 5 mM | 0.3819 mL | 1.9096 mL | 3.8192 mL |
| 10 mM | 0.191 mL | 0.9548 mL | 1.9096 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
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