product name PF-03814735
Description: PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1. PF-03814735 is an orally bioavailable, ATP-competitive Aurora kinase inhibitor with potential antineoplastic activity. Aurora kinase inhibitor PF-03814735 binds to and inhibits Aurora kinases A and B, which may result in the inhibition of cellular division and proliferation in tumor cells that overexpress these kinases. Aurora kinases are serine-threonine kinases that play essential roles in mitotic checkpoint control during mitosis.
References: Mol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9.
474.48
Formula
C23H25F3N6O2
CAS No.
942487-16-3
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 0.4 mg/mL (0.84 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0: ~30 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19393879
| In Vitro |
In vitro activity: In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 ~ 50 nM), and phospho-Aurora2 (with IC50 ~150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735. Kinase Assay: Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of 33P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead. Cell Assay: Cell lines (HCT-116 cell) are grown in appropriate media and evaluated after 48 h of exposure to either PF-03814735 or vehicle, followed by cell number determination in a Coulter Counter. Proliferation (as measured by an increase in cell number) is expressed as a percent of untreated controls. To evaluate the PF-03814735 exposure time required for antiproliferative activity, HL-60 cell cultures are cultured in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposed to various PF-03814735 concentrations for 4, 8, 12, 24, and 48 hours, followed by a washout step and incubation with growth media without PF-03814735 for the remainder of the 72-h assay period. Continuous exposure to PF-03814735 for 72 hours is also evaluated. Cell counts are determined by a Coulter Counter. |
|---|---|
| In Vivo | Once-daily oral dosing of ≥20 mg/kg of PF-03814735 for 10 days to mice bearing HCT-116 xenografts resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The inhibition is associated with a reduction in phosphorylated histone H3 levels. Significant single-agent antitumor efficacy is observed in five additional xenograft tumor models, including A2780 ovarian carcinoma, MDA-MB-231 breast carcinoma, colo-205 and SW620 colorectal carcinomas, and HL-60 acute promyelocytic leukemia. In vivo experiments with two SCLC xenograft models confirms the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. |
| Animal model | HCT116 tumors are implanted s.c. on the right flank of nude mice. |
| Formulation & Dosage | Dissolved in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)]; 10, 20, 30 mg/kg; Oral gavage |
| References | Mol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9. |
Related Posts
product name PF-03814735
Description: PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1. PF-03814735 is an orally bioavailable, ATP-competitive Aurora kinase inhibitor with potential antineoplastic activity. Aurora kinase inhibitor PF-03814735 binds to and inhibits Aurora kinases A and B, which may result in the inhibition of cellular division and proliferation in tumor cells that overexpress these kinases. Aurora kinases are serine-threonine kinases that play essential roles in mitotic checkpoint control during mitosis.
References: Mol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9.
474.48
Formula
C23H25F3N6O2
CAS No.
942487-16-3
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 0.4 mg/mL (0.84 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0: ~30 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19393879
| In Vitro |
In vitro activity: In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 ~ 50 nM), and phospho-Aurora2 (with IC50 ~150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735. Kinase Assay: Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of 33P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead. Cell Assay: Cell lines (HCT-116 cell) are grown in appropriate media and evaluated after 48 h of exposure to either PF-03814735 or vehicle, followed by cell number determination in a Coulter Counter. Proliferation (as measured by an increase in cell number) is expressed as a percent of untreated controls. To evaluate the PF-03814735 exposure time required for antiproliferative activity, HL-60 cell cultures are cultured in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposed to various PF-03814735 concentrations for 4, 8, 12, 24, and 48 hours, followed by a washout step and incubation with growth media without PF-03814735 for the remainder of the 72-h assay period. Continuous exposure to PF-03814735 for 72 hours is also evaluated. Cell counts are determined by a Coulter Counter. |
|---|---|
| In Vivo | Once-daily oral dosing of ≥20 mg/kg of PF-03814735 for 10 days to mice bearing HCT-116 xenografts resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The inhibition is associated with a reduction in phosphorylated histone H3 levels. Significant single-agent antitumor efficacy is observed in five additional xenograft tumor models, including A2780 ovarian carcinoma, MDA-MB-231 breast carcinoma, colo-205 and SW620 colorectal carcinomas, and HL-60 acute promyelocytic leukemia. In vivo experiments with two SCLC xenograft models confirms the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. |
| Animal model | HCT116 tumors are implanted s.c. on the right flank of nude mice. |
| Formulation & Dosage | Dissolved in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)]; 10, 20, 30 mg/kg; Oral gavage |
| References | Mol Cancer Ther. 2010 Apr;9(4):883-94; Mol Cancer Ther. 2012 Mar;11(3):710-9. |