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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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PD153035 is a potent and specific inhibitor of EGFR with Ki and IC50 of 5.2 pM and 29 pM, respectively. |
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Targets
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EGFR |
EGFR |
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IC50 |
5.2 pM (Ki) |
29 pM [1] |
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In Vitro
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PD 153035 shows a potent and selective inhibitory effect on tyrosine phosphorylation induced with EGF with IC50 of 15 nM and 14 nM in Swiss 3T3 fibroblast and A-431 human epidermoid carcinoma cells, respectively. [1] PD153035 shows growth inhibitory effects in cultures of EGF receptor-overexpressing human cancer cell lines including A431, Difi, DU145, MDA-MB-468 and ME180 cells with IC50 of 0.22 μM, 0.3μM, 0.4 μM, 0.68 μM and 0.95 μM, respectively. [2] PD153035 induces a dose-dependent growth inhibition in nasopharyngeal carcinoma (NPC) cells including NPC-TW01, NPC-TW04, and HONE1 cell lines with IC50 of 12.9 μM, 9.8 μM and 18.6μM, respectively. [3] A recent study shows that PD153035 abolishes COX-2 expression induced by the PAR(2)-activating peptide 2-furoyl-LIGRLO-NH(2) (2fLI) in Caco-2 colon cancer cells. [4] |
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In Vivo
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In A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice, PD153035 at 80 mg/kg inhibit EGF receptor tyrosine kinase activity. [5] PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice. [6] Pretreatment of EGFR inhibitors by 24 hours significantly enhances the cytotoxic effect of doxorubicin, paclitaxel, cisplatin, and 5-fluororuacil in NPCTW04 cells. [3] |
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Clinical Trials
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Features
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Protocol
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Kinase Assay
[1]
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| Inhibition of EGF receptor tyrosine kinase |
Enzyme reactions are performed in a total volume of 0.1 mL containing 25 mM Hepes (pH 7.4), 5 mM MgCl2, 2 mM MnCl2, 50 μM sodium vanadate, 0.5 to 1.0 ng of enzyme (which also contains enough EGF to make the final concentrations 2 μg/mL), 10 μM ATP containing 1 μCi of [32P]ATP, varying concentrations of PD153035, and 200 μM of a substrate peptide based on a portion of phospholipase C-γl having the sequence Lys-His-Lys-Lys-Leu-Ala-Glu-Gly-Ser-Ala-Tyr472-Glu-Glu-Val. The reaction is initiated by the addition of ATP. After 10 minutes at room temperature, the reaction is terminated by addition of 2 mL of 75 mM phosphoric acid, and the solution is passed through a 2.5-cm phosphocellulose filter disk that binds the peptide. The filter is washed five times with 75 mM phosphoric acid and placed in a vial with 5 mL of scintillation fluid. The uninhibited control activity produces approximately 100,000 cpm. |
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Cell Assay
[2]
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| Cell Lines |
A431, Difi, DU145, MDA-MB-468 and ME180 |
| Concentrations |
0-3 μM |
| Incubation Time |
72 hours |
| Methods |
Cells are seeded in sixwell plates. The next day, cells are changed to medium containing 0.5% FBS for 18 hours, and then PD153035 is added at various concentrations to the cultures. After 72 hours of treatment, cells are washed once with PBS, harvested with 0.1% human trypsin-l mM EDTA in PBS, and counted with a Coulter counter. The CMK cells grow in suspension and, therefore, do not require trypsinization. |
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Animal Study
[5]
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| Animal Models |
A431 cells are injected into the outbred nude mice. |
| Formulation |
PD153035 is dissolved in water. |
| Doses |
≤80 mg/kg |
| Administration |
Administered via i.p. |
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References |
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[1] Fry DW, et al. Science. 1994, 265(5175), 1093-1095.
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[2] Bos M, et al. Clin Cancer Res. 1997, 3(11), 2099-2106.
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[3] Hsu CH, et al. Oncology. 2005, 68(4-6), 538-547.
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[4] Hirota CL, et al. Am J Physiol Gastrointest Liver Physiol. 2012 Apr 19.
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[5] Kunkel MW, et al. Invest New Drugs. 1996, 13(4), 295-302.
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[6] Prada PO, et al. Diabetes. 2009 , 58(12), 2910-2919.
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