PHT-427 is a novel small-molecule inhibitor of PDPK1/Akt signaling with significant antitumor activity and minimal toxicity in vivo. The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. PHT-427 binds selectively to the PH domain of AKT, causing apoptosis at low micromolar concentrations. And it also binds to the PH domain of PDPK1. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. PHT-427 induces apoptosis (IC50 = 6.3 μM), mainly on Akt Ser473 residue and less strongly on the Akt Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells (IC50 = 65 μM).
| Cell Experiment | |
|---|---|
| Cell lines | Human MiaPaCa-2, BxPC-3, and Panc-1 pancreatic cancer cells |
| Preparation method | Cell cytotoxicity assay Cell growth inhibition was determined using a micro-cytoxicity assay. Cells were plated in 96-well micro-cytoxicity at 5,000–10,000 cells per well (depending on cell doubling time) and grown for 7 days. Compounds dissolved in DMSO were added directly to the media, at various concentrations ranging from 1 to 50 μM. The endpoint was spectrophotometric determination of the protein content of each well using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. A concentration-response relationship at two or more concentration levels was used to obtain an IC50 for the compound. |
| Concentrations | 1~50 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | BxPC-3, Panc-1, MiaPaCa-2, PC-3, SKOV-3, A-549 or MCF-7 cells tumour model in female scid mice |
| Formulation | 40 to 50 mg/ml in sesame seed oil |
| Dosages | 200 mg/kg twice daily for 10 days |
| Administration | oral |
| Molecular Weight | 409.61 |
| Formula | C20H31N3O2S2 |
| CAS Number | 1191951-57-1 |
| Solubility (25°C) | DMSO 80 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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