CH5132799 is a novel and potent class I PI3K inhibitor with IC50 value of 0.014 μM. The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in vitro kinase assays. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.
| Cell Experiment | |
|---|---|
| Cell lines | breast, ovarian, prostate, and endometrial cancer cell lines |
| Preparation method | Cell proliferation assay The cell lines were added to the wells of 96-well plates containing 0.076 to 10,000 nmol/L CH5132799 and incubated at 37°C. After 4 days of incubation, Cell Counting Kit-8 solution (AbMole) was added and, after incubation for several more hours, absorbance at 450 nm was measured with Microplate-Reader iMark (Bio-Rad Laboratories). The antiproliferative activity was calculated by the formula (1 − T/C) × 100 (%), in which T and C represent absorbance at 450 nm of the cells treated with drugs (T) and that of untreated control cells (C). The IC50 values were calculated by using Microsoft Excel 2007. |
| Concentrations | 0.076 to 10,000 nmol/L |
| Incubation time | 4 days |
| Animal Experiment | |
|---|---|
| Animal models | mouse bearing xenograft model of breast cancer KPL-4(PIK3CA H1047R) and BT-474(PIK3CA K111N) and SKOV3 (PIK3CA H1047R)cells |
| Formulation | saline |
| Dosages | 12.5 mg/kg once a day |
| Administration | orally |
| Molecular Weight | 377.42 |
| Formula | C15H19N7O3S |
| CAS Number | 1007207-67-1 |
| Solubility (25°C) | DMSO 12 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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