Home PI3K/Akt/mTOR PI3K inhibitor PKI-402

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PKI-402 PI3K inhibitor

Cat.No.S2739

PKI-402 is a potent dual pan-PI3K/mTOR inhibitor targeting PI3Kα/β/γ/δ and mTOR with IC50 of 2 nM/7 nM/16 nM/14 nM and 3 nM, respectively; this compound is also potent to PI3Kα mutants E545K and H1047R.
PKI-402 PI3K inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 570.65

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SF9 insect cells Function assay 2 h Inhibition of human PI3Kalpha expressed in SF9 insect cells after 2 hrs by fluorescence polarization assay, IC50=0.001 μM
MDA-MB-361 cells Function assay 4 h Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells after 4 hrs by Western blotting, IC50=0.005 μM
PC3 cells Cytotoxicity assay 72 h Cytotoxicity against human PC3 cells with PTEN mutant after 72 hrs, IC50=0.021 μM
Click to View More Cell Line Experimental Data

Chemical Information, Storage & Stability

Molecular Weight 570.65 Formula

C29H34N10O3

 Storage (From the date of receipt)
CAS No. 1173204-81-3 Download SDF Storage of Stock Solutions

Synonyms N/A 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

Solubility

In vitro
Batch:

DMSO : 0.5 mg/mL (0.87 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

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Mechanism of Action

Targets/IC50/Ki
PI3Kα [1]
(Cell-free assay)
2 nM
mTOR [1]
(Cell-free assay)
3 nM
PI3Kβ [1]
(Cell-free assay)
7 nM
PI3Kδ [1]
(Cell-free assay)
14 nM
PI3Kγ [1]
(Cell-free assay)
16 nM
In vitro
Equivalent to the IC50 for wild-type PI3Kα, PKI-402 inhibits E545K and H1047R PI3Kα mutants with IC50 of 3 nM. In a panel of 236 human protein kinases, this compound only displays inhibitory activity against C-Raf and B-Raf with IC50 of 7 μM, and displays little activity against all other kinases with IC50 of > 10 μM. It inhibits the growth of human tumor cell lines with IC50 of 6-349 nM. Consistently, this chemical inhibits phosphorylation of PI3K and mTOR effector proteins, particularly phosphorylated Akt (p-Akt) at T308 and S473 with IC50 of <10 nM and <30 nM, respectively. It inhibits both p70S6K and 4EBP1 phosphorylation with IC50 of <10 nM. This inhibitor also blocks Akt phosphorylation of PRAS40 at T246 with IC50 of <30 nM, and inhibits Akt phosphorylation of ENOS at S1177 and GSK3α/GSK3β at S9/S21 with IC50 of <10 nM. In MDAMB-361, a breast tumor line with mutant PI3K-α (E545K) and elevated levels of Her2 receptor, treatment with this compound induces cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. Less than 10% of MDAMB-361 cells exposed to it at 0.3 μM (or higher) for 24 hours remain viable. [1]
Kinase Assay
Fluorescence polarization format assay
Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. Assay reaction buffer is 20 mM Hepes, pH 7.5, 2 mM MgCl2, 0.05% CHAPS, and 0.01% βME. Assay STOP/detection buffer is 100 mM Hepes, pH 7.5, 4 mM EDTA, 0.05% CHAPS. FP assays are run in Nunc 384-well black polypropylene fluor plates. The FP reaction is run in 20 μL of reaction buffer containing 20 μM PIP2, 25 μM ATP, and >4% DMSO. The reaction is run for 30 minutes at room temp. The reaction is stopped with 20 μL of STOP/detection buffer containing 10 nM probe and 40 nM GST-GRP. Assay plates are incubated for 2 hours, and fluorescence polarization is measured in a Perkin-Elmer Envision plate reader with TAMRA-FP filters.
In vivo
Single dose of PKI-402 (100 mg/kg) suppresses Akt phosphorylation (at T308) and induces cleaved PARP in MDA-MB-361 tumors. In normal tissue (heart and lung), this compound has minimal effect on p-Akt, with no detectable cleaved PARP. Consistently, this chemical at 100 mg/kg (daily for 5 days, one round) reduces initial tumor volume of 260 mm3 to 129 mm3 and prevents tumor regrowth for 70 days in MDA-MB-361. It significantly inhibits the growth of A549 tumors in nude mice at 25 mg/kg and 50 mg/kg. This compound at 100 mg/kg (daily for 5 days, one round) causes significant (P < 0.01) reduction in tumor growth of U87MG. [1]
References

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