PIK-75 HCl

Catalog No.S1205

PIK-75 HCl Chemical Structure

Molecular Weight(MW): 488.74

PIK-75 HCl is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM in cell-free assays.

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Cited by 23 Publications

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Biological Activity

Description PIK-75 HCl is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM in cell-free assays.
Features PI3K and DNA-PK inhibitor.
Targets
DNA-PK [2]
(Cell-free assay)
p110α [1]
(Cell-free assay)
p110γ [1]
(Cell-free assay)
p110δ [1]
(Cell-free assay)
2 nM 5.8 nM 76 nM 0.51 μM
In vitro

PIK-75 shows the impressive potency and isoform selectivity at p110α while the corresponding IC50 values are 1300 nM, 76 nM and 510 nM for other PI3K isoforms, p110β, -γ, and -δ, respectively. Furthermore, when binding to purified p110α, PIK-75 is a noncompetitive inhibitor with respect to ATP with Ki of 36 nM and competitive with respect to the substrate PI with Ki of 2.3 nM. [1] PIK-75 also shows potent inhibition of DNA-PK. [2] PIK-75 (1 μM) reduces cell survival by significantly decreasing mitochondrial activity in unstimulated nonasthmatic airway smooth muscle (ASM) cells, asthmatic ASM cells, and lung fibroblasts. While in TGFβ-stimulated ASM cells, PIK75 only decreases mitochondrial activity in asthmatic cells without effects in nonasthmatic cells. [3] A recent study shows that PIK-75 (10 nM) inhibits TNF-α-induced CD38 mRNA expression and significantly attenuates of TNF-α-induced ADP-ribosyl cyclase activity in human airway smooth muscle cells. [4]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MV4-11 cells MXfDfZRwfG:6aXRCpIF{e2G7 NWH5XpgxPzJiaB?= MYLDfZRwfG:6aXPpeJkh[WejaX7zeEBpfW2jbjDNWlQuOTFiY3XscJMh[W[2ZYKgO|IhcHK|IHL5JGNmdGyWaYTldk1IdG9iYYPzZZktKEmFNUC9NE4xODNizszN M4TubVI3OzR7NkK3
human NZOV9 cells NGr2eFFRem:uaX\ldoF1cW:wIHHzd4F6 NW\YRZJDSW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDOXm9XQSClZXzsd{whUUN3ME2wMlA3PiEQvF2= NFHUeIUyPzh4OUWyNi=>
human NZB5 cells MnrtVJJwdGmoZYLheIlwdiCjc4PhfS=> NFztNppCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIF7aRlUh[2WubIOsJGlEPTB;MD6wOlkh|ryP MXqxO|g3QTV{Mh?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-AKT / AKT ; 

PubMed: 23077605     


Freshly isolated islets treated with PIK-75 at the indicated concentrations for 30 min were subjected to immunoblotting using anti-Phospho-Akt and anti-Pan-Akt antibodies. Phospho-Akt signal intensity normalized to control was quantified (n = 3 for each group). 

MYCN / p-rpS6 ; 

PubMed: 26029667     


Kelly MYCN-amplified neuroblastoma cells were treated for 24 h with the indicated concentrations of inhibitor (PIK-75 or PW-12) and blotted for MYCN and markers downstream of PI3K (pAKT) and mTOR (prpS6).

p-AKT / AKT / p-GSK3β / GSK3β / PARP / Survivin / XIAP ; 

PubMed: 24366069     


(C and D) MIA PaCa-2 cells were treated with PIK-75 as indicated. Western blot analysis was performed with indicated antibodies. (C) GSK3β used as a loading control. (D) β-actin was used as a loading control.

23077605 26029667 24366069
Growth inhibition assay
Cell viability; 

PubMed: 24366069     


MIA PaCa-2 and AsPC-1 cells were treated with increasing concentration of PIK-75 for 48 h and the cell viability was determined by MTT assay. Data are presented as mean ± SD from three independent experiments performed in triplicate.

24366069
Immunofluorescence
Ac-tubulin; 

PubMed: 23873844     


S9 and IB3 cells were either treated with vehicle or 0.5 μM PIK-75 for 24 h. Cells were immunostained with Ac-tub antibodies (red) and DAPI (blue). Representative images are shown from 4 experiments. 

23873844
In vivo In the ErbB3WT tumor model, PIK-75 reduces in vitro chemotactic response to HRGβ1 and lowers pAkt levels by 40%. Besides, PIK-75 significantly reduces tumor cell motility and in vivo invasion in ErbB3WT primary tumors. [5] In the CD1 male mice, PIK-75 leads to serious impairments in the insulin tolerance test (ITT) and glucose tolerance test (GTT), and an increase in glucose production during a pyruvate tolerance test (PTT). [6]

Protocol

Kinase Assay:[1]
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Inhibition Assays:

The PI3K inhibitor PIK-75 is dissolved at 10 mM in dimethyl sulfoxide and stored at −20°C until use. PI3K enzyme activity is determined in 50 μL of 20 mM HEPES, pH 7.5, and 5 mM MgCl2 containing 180 μM phosphatidyl inositol, with the reaction started by the addition of 100 μM ATP (containing 2.5 μCi of [γ-32P]ATP). After a 30-minute incubation at room temperature, the enzyme reaction is stopped by the addition of 50 μL of 1 M HCl. Phospholipids are then extracted with 100 μL of chloroform/methanol [1:1 (v/v)] and 250 μL of 2 M KCl followed by liquid scintillation counting. Inhibitors are diluted in 20% (v/v) dimethyl sulfoxide to generate a concentration versus inhibition of enzyme activity curve, which is then analyzed with the use of Prism version 5.00 for Windows to calculate the IC50. For kinetic analysis, a luminescent assay measuring ATP consumption is used. PI3K enzyme activity is determined in 50 μL of 20 mM HEPES, pH 7.5, and 5 mM MgCl2 with PI and ATP at various concentrations. After a 60-minute incubation at room temperature, the reaction is stopped by the addition of 50 μL of Kinase-Glo followed by a further 15-minute incubation. Luminescence is then read using a Fluostar plate reader. Results are analyzed using Prism.
Cell Research:[3]
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  • Cell lines: A2780, A2780/cp70, 2780AD, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852 cells
  • Concentrations: 0-10 μM
  • Incubation Time: 48 hours
  • Method: Mitochondrial activity is assessed after stimulation with TGFβ with or without inhibitors for 48 hours using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Harvested washed cells are resuspended in DMEM-lO% FCS and aliquoted (500 μL) into 24-well cluster plates prior to serial dilution (1:2) in duplicates. To each well, 100 μL of an appropriate MTT concentration (dissolved in PBS and filtered through a 0.2 μm filter before use to remove any blue formazan product) is added immediately after diluting the cells, which are then incubated for 3.5 hours at 37 °C. The resulting blue formazan product is solubilized overnight (16 hours) at 37 °C by the addition of 500 μL of 10% sodium dodecyl sulfate (SDS) in 0.01 M HCl to each well. A sample (150 μL) from each duplicate well is transferred to a 96-well microplate, and the optical density determinedby automated spectrophotometry against a reagent blank (no cells). Absorbance is measured at a test wavelength of 570 nm and a reference wavelength of 690 nm. For each primary cell culture, results from three to six wells from each treatment are averaged, and data are expressed as absorbance 570 to 690 nm.
    (Only for Reference)
Animal Research:[5]
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  • Animal Models: MTLn3 cells are injected into the right fourth mammary fat pad from the head of female severe-combined immunodeficient/NCr mice.
  • Formulation: PIK-75 is dissolved in DMSO and then diluted in PBS.
  • Dosages: ≤1 μM
  • Administration: Administered via i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 4 mg/mL warmed (8.18 mM)
Water Insoluble
Ethanol 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.

Chemical Information

Molecular Weight 488.74
Formula

C16H14BrN5O4S.HCl

CAS No. 372196-77-5
Storage powder
in solvent
Synonyms N/A

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID