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Purity: ≥98%
PKI-402 is a novel, potent, dual and pan-inhibitor of PI3K/mTOR (phosphatidylinositol 3-kinase/mammalian target of rapamycin) with potential anticancer activity. It inhibits PI3Kα/β/γ/δ and mTOR with an IC50 of 2 nM/7 nM/16 nM/14 nM and 3 nM, respectively to exert its effects.
| Targets |
PI3Kα (IC50 = 2 nM); PI3Kα-H1047R (IC50 = 3 nM); PI3Kα-E545K (IC50 = 3 nM); PI3Kβ (IC50 = 7 nM); PI3Kδ (IC50 = 14 nM); PI3Kγ (IC50 = 16 nM); mTOR (IC50 = 3 nM)
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| ln Vitro |
PKI-402 is an equipotent inhibitor of class I PI3K, including the E545K and H1047R PI3K-α mutants (IC50=2, 3 and 3 nM for PI3Kα, PI3Kα-H1047R and PI3Kα-E545K, respectively). PKI-402 inhibits the growth of human tumor cell lines derived from a variety of human tumor tissues, including breast, brain (glioma), pancreatic, and non-small cell lung cancer (NSCLC) tissues. MDA-MB-361 [breast: Her2+ and PIK3CA mutant (E545K)] is inhibited by PKI-402 with an IC50 of 6 nM. HCT116 (a K-Ras and PIK3CA mutant) is inhibited by PKI-402 with an IC50 of 33 nM[1].
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| ln Vivo |
PKI-402 displays antitumor activity (i.v. route) in breast [MDA-MB-361: Her2+ and PIK3CA (E545K)], glioma (U87MG and PTEN), and NSCLC (A549; K-Ras and STK11) xenograft models. In the MDA-MB-361 xenograft model, PKI-402 results in regression. The strongest PKI-402 effect is seen at 100 mg/kg (daily for 5 days, one round), which decreases initial tumor volume and inhibits tumor regrowth for 70 days. PKI-402 induces cleaved PARP and completely suppresses p-Akt at the T308 and S473 sites at 8 hours in MDA-MB-361 tumor tissue at a dose of 100 mg/kg. P-Akt suppression and cleaved PARP[1] are still present after 24 hours.
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| Enzyme Assay |
Enzyme assays are done in fluorescent polarization (FP) format. In Sf9, human class I PI3Ks and PI3K-mutants (E545K and H1047R) are generated. Escherichia coli produces GST-GRP1 (murine), which GST-Sepharose is used to isolate. The reaction and stop/detection buffers for the assay are composed of 20 mM HEPES (pH 7.1), 2 mM MgCl2, 0.05% CHAPS, and 0.01% -mercaptoethanol, respectively. In 20 L of reaction buffer containing 20 M phosphatidylinositol 4,5-bisphosphate (PIP2), 25 M ATP, and 4% DMSO (compound solvent), the FP reaction is run for 30 min at room temperature. FP reaction is stopped with 20 μL of stop/detection buffer (10 nM probe and 40 nM GST-GRP), and after 2 h, data are collected. Selectivity of PKI-402 is evaluated in the 236 human kinase panel at [ATP]=Km for each enzyme[1].
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| Cell Assay |
MDA-MB-361, MDA-MB-468, T47D, MCF7, BT474, HT29, HCT116, DLD1, U87MG, H157, NCI-H460, A549, NCI-H1975, NCI-H1650, NCI-H2170, KB, 786-0, A498, MIA-PaCa-2, and PC3 cell lines are propagated at 37°C in 5% CO2 incubators in supplier-recommended growth medium. With the CellTiter 96 AQueous proliferation assay, cell growth inhibition is identified. Using a Wallac Victor2 V 1420 multilabel HTS counter, data are gathered 72 hours after the experiment. Utilizing a Cellomics ArrayScan VTI Reader, FOXO-GFP translocation in U2OS cells is measured 60 minutes after exposure to PKI-402[1].
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| Animal Protocol |
Mice: PKI-402 or vehicle is given via intravenous route. Use is made of naked mice with MDA-MB-361 tumors. A tumor's weight is determined. Female nude mice with tumors were given PKI-402 and underwent pharmacodynamic (biomarker) measurements. Animals that have been put to sleep have their tumor or normal tissue samples removed, homogenized, and then twice washed with cold (4°C) PBS before being treated with cell lysis buffer[1].
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| References |
| Molecular Formula |
C29H34N10O3
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|---|---|
| Molecular Weight |
570.64546
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| Exact Mass |
570.2815
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| Elemental Analysis |
C, 61.04; H, 6.01; N, 24.55; O, 8.41
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| CAS # |
1173204-81-3
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| Related CAS # |
1173204-81-3
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| Appearance |
Solid powder
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| SMILES |
CCN1C2=C(C(=NC(=N2)C3=CC=C(C=C3)NC(=O)NC4=CC=C(C=C4)C(=O)N5CCN(CC5)C)N6CCOCC6)N=N1
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| InChi Key |
ZAXFYGBKZSQBIV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H34N10O3/c1-3-39-27-24(34-35-39)26(37-16-18-42-19-17-37)32-25(33-27)20-4-8-22(9-5-20)30-29(41)31-23-10-6-21(7-11-23)28(40)38-14-12-36(2)13-15-38/h4-11H,3,12-19H2,1-2H3,(H2,30,31,41)
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| Chemical Name |
1-[4-(3-ethyl-7-morpholin-4-yltriazolo[4,5-d]pyrimidin-5-yl)phenyl]-3-[4-(4-methylpiperazine-1-carbonyl)phenyl]urea
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| Synonyms |
PKI402; PK-I402; PKI 402
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~0.4 mg/mL (~0.7 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1.43 mg/mL (2.51 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 30% PEG400+0.5% Tween80+5%Propylene glycol: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7524 mL | 8.7619 mL | 17.5239 mL | |
| 5 mM | 0.3505 mL | 1.7524 mL | 3.5048 mL | |
| 10 mM | 0.1752 mL | 0.8762 mL | 1.7524 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
In vitro profile of PKI-402. MDA-MB-361 [Her2+/PIK3CA (E545K)] cells were exposed to PKI-402 (0.003–0.3 μmol/L) for 4 h. Mol Cancer Ther, 2010, 9(4), 976-984. |
PKI-402 suppression of p-Akt-T308, induction of cleaved PARP, and activation of caspase-3/7 alone, and with 0.1 μmol/L PD0325901 (MEK) in HCT116 (K-Ras and |
PIK3CA) at 24 h. In vivo efficacy against MDA-MB-361 xenografts and in vivo biomarkers in tumor and heart tissue. |
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