942487-16-3
942487-16-3 structure
- Name: pf-03814735
- Chemical Name: pf-03814735
- CAS Number: 942487-16-3
- Molecular Formula: C23H25F3N6O2
- Molecular Weight: 474.479
- Catalog: Biochemical Inhibitor Cell Cycle Aurora Kinase Inhibitor
- Create Date: 2019-01-01 10:01:23
- Modify Date: 2024-01-07 18:14:37
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PF-03814735 is a potent, orally available and reversible aurora A and aurora B inhibitor with IC50s of 0.8 and 0.5 nM, respectively.
| Name | pf-03814735 |
|---|---|
| Synonyms |
N-{2-[(1R,8S)-4-{[4-(Cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino}-11-azatricyclo[6.2.1.0]undeca-2,4,6-trien-11-yl]-2-oxoethyl}acetamide
cc-272 Acetamide, N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]- Kinome_1769 |
| Description | PF-03814735 is a potent, orally available and reversible aurora A and aurora B inhibitor with IC50s of 0.8 and 0.5 nM, respectively. |
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| Related Catalog | |
| Target |
Aurora 1:0.8 nM (IC50) Aurora 2:5 nM (IC50) Flt-1:10 nM (IC50) FAK:22 nM (IC50) TrkA:30 nM (IC50) Met:100 nM (IC50) FGFR1:100 nM (IC50) |
| In Vitro | In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells[1]. 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[2]. |
| In Vivo | Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition[1]. PF-03814735 is much more effective in NCI-H82 xenografts when administered on a weekly dosing schedule at 80 mg/kg compared with a daily schedule at 15 mg/kg. PF-03814735 delayed growth by 23.5 days on the weekly schedule, which corresponds to 0.9 logs of net cell kill during the course of treatment[2]. |
| 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 at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 min, at a substrate peptide concentration of 2 μM. 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 is measured by capturing the peptide on a streptavidin scintillation proximity assay bead[1]. |
| Cell Assay | Cell lines are grown in appropriate media and evaluated after 48 h of exposure to either PF-03814735 or vehicle. 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 h, 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 h is also evaluated. Cell counts are determined by a Coulter Counter[1]. |
| Animal Admin | Mice: Mice bearing s.c. HCT-116 xenograft tumors (250-400mm3) are evaluated for plasma drug concentrations and tumor levels of phosphohistone H3 Ser10. Mice are treated with a single dose of PF-03814735 or vehicle by oral gavage and are sacrificed at 0.5, 1, 2, 3, 7, 16, or 24 h postdose (3-4 mice/time point)[1]. |
| References |
| Density | 1.4±0.1 g/cm3 |
|---|---|
| Molecular Formula | C23H25F3N6O2 |
| Molecular Weight | 474.479 |
| Exact Mass | 474.199097 |
| PSA | 99.25000 |
| LogP | 2.11 |
| Appearance | white to beige |
| Index of Refraction | 1.642 |
| Storage condition | ?20°C |
| Water Solubility | DMSO: soluble20mg/mL, clear |
| RIDADR | NONH for all modes of transport |
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