PKI-402

Catalog No.S2739 Batch:S273902

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Technical Data

Formula

C29H34N10O3
Molecular Weight 570.65 CAS No. 1173204-81-3
Solubility (25°C)* In vitro DMSO 0.5 mg/mL (0.87 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description 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; also potent to PI3Kα mutants E545K and H1047R.
Targets
PI3Kα [1]
(Cell-free assay)		 mTOR [1]
(Cell-free assay)		 PI3Kβ [1]
(Cell-free assay)		 PI3Kδ [1]
(Cell-free assay)		 PI3Kγ [1]
(Cell-free assay)
2 nM 3 nM 7 nM 14 nM 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, PKI-402 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. PKI-402 inhibits the growth of human tumor cell lines with IC50 of 6-349 nM. Consistently, PKI-402 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. PKI-402 inhibits both p70S6K and 4EBP1 phosphorylation with IC50 of <10 nM. PKI-402 inhibits 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, PKI-402 treatment induces cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. Less than 10% of MDAMB-361 cells exposed to PKI-402 at 0.3 μM (or higher) for 24 hours remain viable. [1]
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), PKI-402 (100 mg/kg) has minimal effect on p-Akt, with no detectable cleaved PARP. Consistently, PKI-402 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. PKI-402 significantly inhibits the growth of A549 tumors in nude mice at 25 mg/kg and 50 mg/kg. PKI-402 at 100 mg/kg (daily for 5 days, one round) causes significant (P < 0.01) reduction in tumor growth of U87MG. [1]

Protocol (from reference)

Kinase Assay:[1]
  • 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.
Cell Assay:[1]
  • 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

  • Concentrations

    Dissolved in DMSO, final concentrations ~3 μM

  • Incubation Time

    72 hours

  • Method

    Cell growth inhibition is determined using the CellTiter 96 Aqueous nonradioactive cell proliferation assay. This homogeneous colorimetric method determined the number of viable cells in proliferation assays. The assay is carried out in 96-well format, with cell number numbers per well being adjusted on the basis of growth characteristics of the various cell lines used. Assay end point data are quantitated after 72 hours of PKI-402 exposure using a Victor2 V (Wallac) model 1420 multilabel HTS counter.
Animal Study:[1]
  • Animal Models

    Female nude mice injected subcutaneously with MDA-361, U87MG, or A549 cells

  • Dosages

    ~100 mg/kg/day

  • Administration

    Administered by i.v. route

Selleck's PKI-402 has been cited by 6 publications

Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response [ Cancer Cell Int, 2024, 24(1):38] PubMed: 38238825
Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival [ Antioxidants (Basel), 2022, 11(3)461] PubMed: 35326111
Dual Inhibition of PI3K/Akt/mTOR Signaling Pathway in Leukemic Cell Lines Upregulates Long Non-Coding RNAs RNCR3, UCA1 and HULC [ Indian Journal of Pharmaceutical Sciences, 2022, 10.36468/pharmaceutical-sciences.spl.584] PubMed: none
PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors [ Cells, 2021, 10(5)1261] PubMed: 34065268
Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids [ Mol Cells, 2021, 44(1):50-62] PubMed: 33455947
Phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 inhibits breast cancer induced osteolysis [Yuan G Cancer Lett, 2019, 443:135-144] PubMed: 30540926

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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