PKI-402 is a selective, reversible, ATP-competitive, equipotent class I phosphatidylinositol 3-kinases (PI3K) inhibitor with IC50 of 1, 7, 16 and 14 nM for PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, respectively. PKI-402 gave rise to in vitro growth inhibition of human tumor cell lines derived from breast, brain (glioma), pancreas, and non small cell lung cancer (NSCLC) tissues. In many cases IC50 values were <100 nM. In vitro, PKI-402 suppressed phosphorylation of PI3K and mTOR effect or proteins, particularly p-Akt at threonine308 (T308), at concentrations that closely matched those that inhibited tumor cell growth. In MDA361, a breast tumor line with elevated levels of Her2 receptor, and mutant PI3K- (E545K), 30 nM PKI-402 triggered cleaved PARP, a marker for apoptosis. In vivo, PKI-402 revealed anti-tumor activity when administered by IV route in glioma (U87MG, PTEN), NSCLC (A549; K-Ras, STK11), and breast (MDA361: Her2+, PIK3CA [E545K]) xenograft models. At 25, 50, and 100 mg/kg PKI-402 caused regression of MDA361 tumors. PKI-402 effect was most pronounced at 100 mg/kg (daily for 5 days, 1 round),which decreased an initial tumor volume of 260 mm3 to 129 mm3, and inhibited tumor re-growth for 70 days. Tumor re-growth occurred between days 16-20 when PKI-402 was administered at 25and 50 mg/kg (dx5, 2 rounds). In MDA-MB-361 [breast: Her2 (+) and PIK3CA mutant (E545K)], 30 nM PKI-402 induced cleaved poly (ADP-ribose) polymerase (PARP), a marker for apoptosis.
| Cell Experiment | |
|---|---|
| Cell lines | MDA-MB-361, MDA-MB-468, T47D, MCF7, BT474, HT29, HCT116, DLD1, U87MG, H157, NCI-H460, A549, NCI-H1975, NCI-H1650, NCIH2170, KB, 786-0, A498, MIA-PaCa-2, and PC3 |
| Preparation method | Determine cell growth inhibition using the CellTiter 96 Aqueous nonradioactive cell proliferation assay. This homogeneous colorimetric method determined the number of viable cells in proliferation assays. Carry out the assay in 96-well format, with cell number numbers per well being adjusted on the basis of growth characteristics of the various cell lines used. After 72 hours of PKI-402 exposure using a Victor2 V (Wallac) model 1420 multilabel HTS counter, quantify assay end point data . |
| Concentrations | Dissolved in DMSO, final concentrations ~3 μM |
| Incubation time | 72 hours |
| Animal Experiment | |
|---|---|
| Animal models | Female nude mice injected subcutaneously with MDA-361, U87MG, or A549 cells |
| Formulation | Dissolved in 0.5% methylcellulose and 0.4% polysorbate 80 (Tween-80) |
| Dosages | ~100 mg/kg/day |
| Administration | Administered by i.v. route |
| Molecular Weight | 570.65 |
| Formula | C29H34N10O3 |
| CAS Number | 1173204-81-3 |
| Solubility (25°C) | 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.
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SNV4818 is a potential best-in-class (best-in-class) mutation-selective PI3K-α inhibitor with excellent selectivity for the H1047X mutant and moderate selectivity for the related E545/542X mutant. |
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hSMG-1 inhibitor 11j, a pyrimidine derivative, is a potent and selective inhibitor of hSMG-1, with an IC50 of 0.11 nM. |
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