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In vitro: E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. E7449 inhibits Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. E7449 stabilizes axin and TNKS proteins resulting in β-catenin de-stabilization and significantly alters expression of Wnt target genes. E7449 inhibits TNKS1 and 2 (PARP5a and 5b) with IC50 values of 50-100 nmol/L. Significant inhibitory activity is not observed for PARP3 or PARPs 6-16 (PARP9 and 13 lack activity and PARP4 had minimal signal. In vivo: Chemotherapy is potentiated by E7449 and single agent has significant antitumor activity in BRCA-deficient xenografts. E7449 lacks single agent antitumor activity in vivo. E7449 antitumor activity is increased through combination with MEK inhibition. Treatment with E7449 at 30 or 100 mg/kg in xenografts is well-tolerated without any significant body weight loss or deaths. Treatment with E7449 at 100 mg/kg resulted in significant PARP inhibition that is sustained for at least 12 hours and recovered to basal levels within 24 h.
| Cell Experiment | |
|---|---|
| Cell lines | Human breast cancer cell lines, HCC1143, HCC70, HCC1806, MDA-MB-436, T47D, MDA-MB-157, MDA-MB-231, MDA-MB-468, MDA-MB-453, BT-20 and Hs578T |
| Preparation method | For proliferation assays cells are plated at low density in 96 well plates. E7449 is added at various concentrations and plates incubated for a total of 8 days; compound and medium are replenished on day 4. Cell growth is assessed. |
| Concentrations | |
| Incubation time | 8 days |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6 mice |
| Formulation | 0.5% methyl cellulose in water |
| Dosages | 30, 100 or 300 mg/kg |
| Administration | oral administration |
| Molecular Weight | 317.34 |
| Formula | C18H15N5O |
| CAS Number | 1140964-99-3 |
| Solubility (25°C) | 4 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related PARP Products |
|---|
| 2-Methylquinazolin-4-ol
2-Methylquinazolin-4-ol is a potent competitive poly(ADP-ribose) synthetase inhibitor, with a Ki of 1.1 μM. 2-Methylquinazolin-4-ol mammalian aspartate transcarbamylase (ATCase) inhibitor, with IC50 of 0.20 mM. |
| DPQ
DPQ is a potent PARP-1 inhibitor. |
| OUL232
OUL232 is a potent inhibitor of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15. |
| AZ3391
AZ3391 is a potent inhibitor of PARP. |
| PARP1-IN-5
PARP1-IN-5 is a low toxicity, orally active, potent and selective PARP-1 inhibitor (IC50 =14.7 nM). |
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