PHT-427

Catalog No.S1556

PHT-427 is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.

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PHT-427 Chemical Structure

PHT-427 Chemical Structure
Molecular Weight: 409.61

Validation & Quality Control

Customer Product Validation(2)

Quality Control & MSDS

Related Compound Libraries

PHT-427 is available in the following compound libraries:

Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description PHT-427 is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.
Targets Akt [1] PDK-1 [1]
IC50 2.7 μM(Ki) 5.2 μM(Ki)
In vitro PH-427 is a pleckstrin homology domain inhibitor to Akt/PDPK1. PH-427 significantly reduces phospho-Ser241-PDPK1 phospho-Thr308-Akt in PC-3 prostate cancer cells at 10 μM, which shows that PHT-427 could inhibit both Akt and PDPK1. PHT-427 also inhibits translocation of the Akt and PDPK1 PH domains in plasma membrane. [1] PHT-427 induces apoptosis and inhibits AKT phosphorylation with IC50 of 8.6 μM (in BxPC-3 cells), which mainly on its Ser473 residue and less strongly on Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells with IC50 of 65 μM. [2]
In vivo PHT-427 shows great antitumor activity in BxPC-3 pancreatic, MCF-7 breast and A-549 NSCL cancer xenografts. PHT-427 gives up to an 80% inhibition of tumor growth in BxPC-3 at doses of 125 to 250 mg/kg. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Surface plasmon resonance (SPR) spectroscopy binding assays All interaction analyses are performed with a Biacore 2000, Biacore 2000 Control Software v3.2, and BIAevaluation v4.1 analysis software. The PH domain GST-fusion proteins (Akt1, IRS1, and PDK1) are immobilized on a CM5 Sensorchip using Biacore's Amine Coupling Kit to a level of 10,000 Response units (RUs). Small molecule analytes at concentrations ranging from 0.1 to 10 × the predicted KD are injected at a high flow rate (30μL/min). DMSO concentrations in all samples and running buffer are 1% (v/v) or less.

Cell Assay: [2]

Cell lines Panc-1 cells
Concentrations 1-50 μM
Incubation Time
Method Cell growth inhibition is determined using a micro-cytoxicity assay. Cells are plated in 96-well micro-cytoxicity at 5-10 × 103 cells per well (depending on cell doubling time) and grown for 7 days. PHT-427 dissolved in DMSO is added directly to the media, at various concentrations ranging from 1 to 50 μM. The endpoint is spectrophotometric determination of the protein content of each well using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. A concentration-response relationship at two or more concentration levels is used to obtain an IC50 for PHT-427.

Animal Study: [1]

Animal Models BxPC-3, Panc-1, MiaPaCa-2, PC-3, SKOV-3, A-549 or MCF-7 cells are injected subcutaneously into the flanks of female scid mice.
Formulation 40 to 50 mg/mL in sesame seed oil
Dosages 125-250 mg/kg
Administration Oral administration

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Meuillet EJ, et al. Mol Cancer Ther, 2010, 9(3), 706-717.

[2] Moses SA, et al. Cancer Res, 2009, 69(12), 5073-5081.

Chemical Information

Download PHT-427 SDF
Molecular Weight (MW) 409.61
Formula

C20H31N3O2S2

CAS No. 1191951-57-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms CS-0223
Solubility (25°C) * In vitro DMSO 82 mg/mL (200.19 mM)
Ethanol 60 mg/mL (146.48 mM)
Water <1 mg/mL (<1 mM)
In vivo 5% DMSO+95% Corn oil 5 mg/mL
* <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.
Chemical Name 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

Customer Product Validation (2)


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Rating
Source Blood 2011 118, 2840-2848. PHT-427 purchased from Selleck
Method Luciferase reporter assays
Cell Lines 32D cells, BCR-ABL cells
Concentrations 20 μM
Incubation Time 24 h
Results Treatment of 32D/BCR-ABL cells withthe AKT/PDPK1 inhibitor PHT-427, the PI3K inhibitor LY294002 or the BCR-ABL inhibitor imatinib substantially reduced Atf5 promoter-directed luciferase activity.

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Rating
Source Eur J Pharmacol 2014 747C, 71-87. PHT-427 purchased from Selleck
Method Western blot
Cell Lines Serum-starved LX-2 human HSCs
Concentrations 20 uM
Incubation Time 4 h
Results The experiments described above suggest that ATG blocks PDGF-BB-induced Akt phosphorylation. To determine whether these effects are responsible for ATG suppressed FOXO3a phosphorylation in PDGF-BB-activated HSCs, cells were incubated with 50 ng/ml PDGF-BB in the presence or absence of PI3K/Akt signaling inhibitors LY294002 and PHT-427. The two inhibitors nearly completely inhibited PDGF-BB-induced phosphorylation of Akt and its downstream target FOXO3a.

Tech Support

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.

Tel: +1-832-582-8158 Ext:3

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