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

Batch: Purity: 99.01%
99.01

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

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

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Mass Concentration Volume Molecular Weight
Dilution Calculator Molecular Weight Calculator

In vivo
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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

Mechanism of Action

Targets/IC50/Ki
PI3Kα
(Cell-free assay)
2 nM
mTOR
(Cell-free assay)
3 nM
PI3Kβ
(Cell-free assay)
7 nM
PI3Kδ
(Cell-free assay)
14 nM
PI3Kγ
(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.
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.
References

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