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 |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related PARP Products |
|---|
| DSB-1522
DSB-1522 is a PARP1 inhibitor that can be used in tumor-related studies. |
| DM-5167
DM-5167 is a PARP1 inhibitor that can be used in studies related to triple negative breast cancer. |
| NMS-03305293
NMS-03305293 is a PARP inhibitor with high selectivity for PARP1 isoforms and low DNA capture effect, which specifically kills BRCA mutated tumor cells. In addition, NMS-03305293 can penetrate the blood-brain barrier and can be used in studies related to CNS tumors and brain metastatic tumors. |
| SNV1521
SNV1521 is a potential best-in-class (BIC), highly selective and CNS-permeable PARP1 inhibitor. |
| Basroparib
Basroparib is an orally active selective inhibitor of end-anchor polymerase (TNKS) and an inhibitor of ribose polymerase (PARP) with antitumor activity. |
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