XL147 (SAR245408) is a novel small molecule PI3K inhibitor. Activation of the PI3 kinase pathway occurs frequently in many cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. XL147 demonstrated cytotoxic activity, with a median relative IC(50) value of 10.9 µM (range 2.7-24.5 µM) in vitro. Also XL147 was well tolerated in vivo, all 44 tested xenograft models were evaluable for efficacy. XL147 (SAR245408) induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6 in HER2(+) cells. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts.
| Cell Experiment | |
|---|---|
| Cell lines | panel of cell lines, such as BT474, PC-3 and MCF-7 |
| Preparation method | Cell-based assays. Cell lines were obtained from the ATCC in 2001–2005 and maintained in culture conditions at 37°C under 5% CO2 as previously described. For PI3K pathway status assessment following EGF treatment, the culture medium was replaced with test compounds dissolved in serum-free DMEM containing 0.3% DMSO. After incubation for 3 hours, cells were stimulated with 100 ng/mL of EGF (R&D Systems, 236-EG) for 10 minutes and Western immunoblot analysis of cell lysates was performed as previously described. Assessment of mTOR pathway status in Ramos cells was performed as previously described. Cellular proliferation was assessed as previously described using the Cell Proliferation ELISA, bromodeoxyuridine (BrdUrd) chemiluminescence kit. |
| Concentrations | 0~30 μM |
| Incubation time | 48 or 72 h |
| Animal Experiment | |
|---|---|
| Animal models | MCF-7 and OVCAR cells tumour xenograft model |
| Formulation | sterile water/10 mmol/L HCl or water |
| Dosages | 30, 100mg/kg qd or 300mg/kg twice weekly |
| Administration | oral gavage |
| Molecular Weight | 448.52 |
| Formula | C21H16N6O2S2 |
| CAS Number | 934526-89-3 |
| Solubility (25°C) | DMSO 10 mg/mL |
| 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.
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