3-tert-butyl-1-(2-{[4-(diethylamino)butyl]amino}-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea

• ChemBase编号: 72601
• 分子式: C28H41N7O3
• 平均质量: 523.67024
• 单一同位素质量: 523.32708821
• SMILES: n1c(nc2c(c1)cc(c(n2)NC(=O)NC(C)(C)C)c1cc(cc(c1)OC)OC)NCCCCN(CC)CC
• Canonical SMILES: CCN(CCCCNc1ncc2c(n1)nc(c(c2)c1cc(OC)cc(c1)OC)NC(=O)NC(C)(C)C)CC
• InChI: InChI=1S/C28H41N7O3/c1-8-35(9-2)13-11-10-12-29-26-30-18-20-16-23(19-14-21(37-6)17-22(15-19)38-7)25(31-24(20)32-26)33-27(36)34-28(3,4)5/h14-18H,8-13H2,1-7H3,(H3,29,30,31,32,33,34,36)
• InChIKey: DXCUKNQANPLTEJ-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 3-tert-butyl-1-(2-{[4-(diethylamino)butyl]amino}-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea
• IUPAC传统名: 3-tert-butyl-1-(2-{[4-(diethylamino)butyl]amino}-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea
• 别名: N-[2-[[4-(Diethylamino)butyl]amino-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N′-(1,1-dimethylethyl)urea; PD 173074; PD173074; N-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea; PD 173074; PD-173074

登记号

• CAS号: 219580-11-7
• MDL号: MFCD08705327
• PubChem SID: 162037526; 24724575
• PubChem CID: 1401

理论计算性质

• Acid pKa: 11.542242
• 质子受体: 8
• 质子供体: 3
• LogD (pH = 5.5): 0.594219
• LogD (pH = 7.4): 1.2788149
• Log P: 3.9098845
• 摩尔折射率: 156.0006 cm^3
• 极化性: 59.41843 Å^3
• 极化表面积: 113.53 Å^2
• 可自由旋转的化学键: 13
• 里宾斯基五规则: false

分子性质

理化性质

• 溶解度: Chloroform; DMSO: soluble21 mg/mL; Methanol
• 外观: yellow solid; Yellow Solid
• 熔点: 98-100°C

安全信息

• 保存条件: -20°C; Refrigerator
• 欧盟危险性物质标志: 刺激性(Irritant) (Xi)
• 德国WGK号: 3
• 危险公开号: 36/37/38
• 安全公开号: 26
• GHS危险品标识: GHS07
• GHS警示词: Warning
• GHS危险声明: H315-H319-H335
• GHS警示性声明: P261-P305 + P351 + P338
• 个人保护装置: dust mask type N95 (US), Eyeshields, Gloves
• 保存温度: 2-8°C

药理学性质

• 作用靶点: FGFR; VEGFR
• 相关基因信息: human ... FGFR1(2260), KDR(3791)mouse ... Pdgfrb(18596)

产品相关信息

• 纯度: ≥98% (HPLC)
• 成盐信息: Free Base
• Empirical Formula (Hill Notation): C28H41N7O3

详细说明

Selleck Chemicals - S1264

Research Area

• Description: Cancer

Biological Activity

• Description: PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM.
• Targets: FGFR1
• IC50: ~25 nM ^[1]
• In Vitro: PD173074 is an ATP-competitive inhibitor of FGFR1 with K_i of ~40 nM. PD173074 is also an effective inhibitor of VEGFR2. Compared to FGFR1, PD173074 weakly inhibits the activities of Src, InsR, EGFR, PDGF, MEK, and PKC with 1000-fold or greater IC50 values. PD173074 inhibits autophosphorylation of FGFR1 and VEGFR2 in a dose-dependent manner with IC50 of 1-5 nM and 100-200 nM, respectively. ^[1] PD173074 inhibits FGF-2 promotion of granule neuron survival in a dose-dependent manner with IC50 of 12 nM, exhibiting 1,000-fold greater potency than that of SU 5402. ^[2] PD173074 specifically inhibits FGF-2-mediated effects on proliferation, differentiation, and MAPK activation in oligodendrocyte (OL) lineage cells. ^[3] PD173074 is active against the WT receptor and FGFR3 mutations in multiple myeloma (MM) cell lines. PD173074 also potently inhibits autophosphorylation of FGFR3 in a dose-dependent manner with IC50 of ~5 nM. PD173074 treatment potently reduces viability of FGFR3-expressing KMS11 and KMS18 cells with IC50 of <20 nm.="" inhibition="" of="" afgf-stimulated="" mm="" cell="" growth="" by="" pd173074="" is="" highly="" correlated="" with="" the="" expression="" of="" fgfr3.="" pd173074="" treatment="" completely="" abolishes="" nih="" 3t3="" transformation="" mediated="" by="" y373c="" fgfr3="" but="" not="" by="" ras="" v12,="" demonstrating="" that="" pd173074="" specifically="" targets="" fgfr3-mediated="" cell="" transformation="" and="" lacks="" nonspecific="" cytotoxic="" effect.="" pd173074="" also="" induces="" functional="" maturation="" of="" kms11="" and="" kms18="" cells.="">^[4]
• In Vivo: Administration of PD173074 at 1 mg/kg/day or 2 mg/ka/day in mice can effectively block angiogenesis induced by either FGF or VEGF in a dose-dependent manner with no apparent toxicity. ^[1] PD173074 inhibits in vivo growth of mutant FGFR3-transfected NIH 3T3 cells in nude mice. Inhibition of FGFR3 by PD173074 delays tumor growth and increases survival of mice in a KMS11 xenograft myeloma model. ^[4] In the H-510 xenograft, oral aministration of PD173074 blocks tumor growth similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. In H-69 xenografts, PD173074 induces complete responses lasting >6 months in 50% of mice. These effects are correlated with increased apoptosis in excised tumors, but not a consequence of disrupted tumor vasculature. ^[5]

Combination Therapy

• Description: In the H-510 xenograft, the anti-tumor effect of cisplatin is significantly potentiated by coadministration of PD173074. ^[5] The combination of PD173074 with paclitaxel or doxorubicin shows synergistic activity in the FGFR2 mutant cell lines. ^[6]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro kinase inhibition assays: Assays using the full-length FGFR-1 kinase are performed in a total volume of 100 μL containing 25 mM HEPES buffer (pH 7.4), 150 mM NaCl, 10 mM MnCl₂, 0.2 mM sodium orthovanadate, 750 μg/mL concentration of a random copolymer of glutamic acid and tyrosine (4:1), various concentrations of PD173074 and 60 to 75 ng of enzyme. The reaction is initiated by the addition of [γ-^32P]ATP (5 μM ATP containing 0.4 μCi of [γ-^32P]ATP per incubation), and samples are incubated at 25°C for 10 minutes. The reaction is terminated by the addition of 30% trichloroacetic acid and the precipitation of material onto glass-fiber filter mats. Filters are washed three times with 15% trichloroacetic acid, and the incorporation of [^32P] into the glutamate tyrosine polymer substrate is determined by counting the radioactivity retained on the filters in a Wallac 1250 betaplate reader. Nonspecific activity is defined as radioactivity retained on the filters following incubation of samples without enzyme. Specific activity is determined as total activity (enzyme plus buffer) minus nonspecific activity. The concentration of PD173074 that inhibits FGFR-1 enzymatic activity by 50% (IC50) is determined graphically.
• Protocol: Cell Assay ^[4]
• Cell Lines: KMS11 and KMS18
• Concentrations: Dissolved in DMSO, final concentrations ~100 nM
• Incubation Time: 48 hours
• Methods: Cells are incubated with increasing concentrations of PD173074 in the presence of aFGF/heparin for 48 hours. The percentage of viable cells is determined by MTT.
• Protocol: Animal Study ^[1]
• Animal Models: Swiss Webster mice with induced corneal angiogenesis
• Formulation: Prepared in sterile fashion
• Doses: ~2 mg/kg/day
• Administration: Administered intraperitoneally

References

• References: [1] Mohammadi M, et al. EMBO J, 1998, 17(20), 5896-5904.
• References: [2] Skaper SD, et al. J Neurochem, 2000, 75(4), 1520-1527.
• References: [3] Bansal R, et al. J Neurosci Res, 2003, 74(4), 486-493.
• References: [4] Trudel S, et al. Blood, 2004, 103(9), 3521-3528.
• References: [5] Pardo OE, et al. Cancer Res, 2009, 69(22), 8645-8651.
• References: [6] Byron SA, et al. Int J Gynecol Cancer, 2012.

Sigma Aldrich - P2499

Biochem/physiol Actions
PD 173074 is a fibroblast growth factor receptor 3 (FGFR3) inhibitor: IC50 = 5 nM inhibition of FGFR3 autophosphorylation. PD 173074 arrests the G0/G1 phase of FGFR3-expressing cells. It is 100-fold more selective for FGFR3 than for VEGF receptors, IGF-1 receptors, and MAPKs.

Toronto Research Chemicals - P217700

PD 173074 is a selective FGFR1 and FGFR3 inhibitor. PD 173074 is a compound induced a dose-dependent reduce in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation.

参考文献

• Mohammadi M, et al. EMBO J, 1998, 17(20), 5896-5904.
• Skaper SD, et al. J Neurochem, 2000, 75(4), 1520-1527.
• Bansal R, et al. J Neurosci Res, 2003, 74(4), 486-493.
• Trudel S, et al. Blood, 2004, 103(9), 3521-3528.
• Pardo OE, et al. Cancer Res, 2009, 69(22), 8645-8651.
• Byron SA, et al. Int J Gynecol Cancer, 2012.
• Mohammadi, M., et al.: Science, 276, 955 (1997)
• Yagasaki, F., et al.: Cancer Res., 61, 8371 (1997)
• Keats, J., et al.: Blood, 101, 1520 (1997)
• Buchler, et al.: 9, 119 (1997)