Inhibitor of tyrosine kinase activity of fibroblast growth factor receptors
PD173074 is a poten and selective fibroblast growth factor receptor (FGFR) inhibitor. Fibroblast growth factor-2 is reported to be able to induce proliferation and chemoresistance in Small cell lung cancer (SCLC) cells.
In vitro: PD173074 was found to block H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevent FGF-2-induced chemoresistance as well. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. In addition, PD173074 showed a high degree of selectivity for FGFR tyrosine kinase [2].
In vivo: In the H-510 xenograft mouse model, tumor growth was significanlty improved similar to that seen with single-agent cisplatin administration. Accordingly, PD173074 treatment resulted in significanlty prolonged median survival when compared with that of control sham-treated animals. More dramatically, PD173074 also induced complete responses lasting >6 months in 50% of in mice H-69 xenografts [2].
Clinical trial: PD173074 is still in the preclinical development stage, and no clinical data are available currently.
参考文献:
[1] Pardo OE, Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, Lemoine NR, Stamp GW, Aboagye EO, Seckl MJ.? The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. Cancer Res. 2009 Nov 15;69(22):8645-51.
[2] Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR.? Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896-904.
| Kinase experiment [1]: | |
|
In vitro kinase inhibition assays |
Assays using the full-length FGFR-1 kinase were 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 was initiated by the addition of [γ-32P]ATP (5 μM ATP containing 0.4 μCi of [γ-32P]ATP per incubation), and samples were incubated at 25 °C for 10 mins. The reaction was terminated by the addition of 30% trichloroacetic acid and the precipitation of material onto glass-fiber filter mats. Filters were washed three times with 15% trichloroacetic acid, and the incorporation of [32P] into the glutamate tyrosine polymer substrate was determined by counting the radioactivity retained on the filters in a Wallac 1250 betaplate reader. |
| Cell experiment [1]: | |
|
Cell lines |
NIH 3T3 cells |
|
Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
|
Reaction Conditions |
0 ~ 1000 nM; 5 mins |
|
Applications |
PD 173074 dose-dependently inhibited autophosphorylation of FGFR1, with an IC50 value in the range of 1 ~ 5 nM. In addition, PD 173074 inhibited autophosphorylation of VEGFR2 with an IC50 value of 100 ~ 200 nM. |
| Animal experiment [1]: | |
|
Animal models |
Swiss Webster mice with induced corneal angiogenesis |
|
Dosage form |
1 or 2 mg/kg/day; i.p. |
|
Applications |
At the dose of 1 or 2 mg/kg, PD 173074 significantly inhibited angiogenesis induced by either FGF or VEGF in a dose-dependent manner. Besides, it showed no apparent toxicity. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
参考文献: [1]. Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896-904. | |
动态评分
0.0