PP1 Chemical Structure

PP1 Chemical Structure
Molecular Weight: 281.36

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Quality Control & MSDS

Src Inhibitors with Unique Features

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  • FDA-approved Src Inhibitor

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  • Newest Src Inhibitor

    PP1 Potent and selective Src inhibitor for Lck/Fyn with IC50 of 5 nM/ 6 nM.

  • Classic Src Inhibitor

    KX2-391 The first clinical Src inhibitor (peptidomimetic class) that targets the peptide substrate site of Src, with GI50 of 9-60 nM in cancer cell lines.

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description PP1 is a potent and selective Src inhibitor for Lck/Fyn with IC50 of 5 nM/ 6 nM.
Targets LCK [1] Fyn [1] Kit [2] EGFR [1]

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IC50 5 nM 6 nM ~75 nM 250 nM
In vitro PP1 is a nano-molar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells (IC50, 0.5 μM), demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation (IC50, 0. 5 μM) over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleu-kin-2 (IL-2)-induced T cell proliferation. PP1 (1 μM) selectively inhibits the induction of the IL-2 gene, but not the granulocyte-macrophage colony-stimulating factor or IL-2 receptor genes. PP1 also inhibits Src (IC50, 170 nM) and Hck (IC50, 20 nM). PP1 is 50–100-fold less active in the inhibition of A-431 epidermal growth factor receptor autophosphorylation (IC50, 0.25 μM). [1] PP1 also inhibits Kit and Bcr-Abl tyrosine kinases with IC50 of ∼75 nM and 1 μM, respectively. PP1 completely abrogates the proliferation of M07e cells in response to SCF with IC50 of 0.5–1 μM. PP1 (1 μM) inhibits SCF-induced c-Kit autophosphorylation in intact cells and blocks the activation of mitogen-activated protein kinase and Akt. PP1 inhibits the activity of mutant constitutively active forms of c-Kit (D814V and D814Y) found in mast cell disorders, and triggers apoptosis in the rat basophilic leukemia cell line RBL-2H3 that expresses mutant c-Kit. PP1 reduces the constitutive activation of signal transducer and activators of transcription 5 and mitogen-activated protein kinase and triggeres apoptosis in FDCP1 cells expressing Bcr-Abl. [2]
In vivo
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Immune complex enzyme assays The acid-treated enolase is diluted 1:20 with 1× PBS before aliquoting 100 mL/well into a Nunc 96-well high protein binding assay plate. Assay wells are then aspirated; blocked with 0.5% bovine serum, 1× PBS for 1 h at 37 ℃;and then washed five times with 300 mL of 1× PBS/well. The source of Lck is either LSTRA cells or Lck expressed in HeLa cells using a vaccinia expression system. FynT is expressed in HeLa cells using the vaccinia system. Cells (12.5× 106/mL) are lysed in lysis buffer (20 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Nonidet P-40, and 23 trypsin inhibitory units/mL aprotinin), and the lysates are clarified by centrifugation at 14,000 cpm for 15 min at 4 ℃ in an Eppendorf tube. The clarified lysates are then incubated with the appropriate anti-kinase antibody at 10 μg/mL for 2 h at 4 ℃. Protein A-Sepharose beads are added to the antibody/lysate mixture at 250 μL/mL and allowed to incubate for 30 min at 4 ℃. The beads are then washed twice in 1 mL of lysis buffer and twice in 1 mL of kinase buffer (25 mM HEPES, 3 mM MnCl2, 5mM MgCl2, and 100 μM sodium orthovanadate) and resuspended to 50% (w/v) in kinase buffer. Twenty-five microliters of the bead suspension is added to each well of the enolase-coated 96-well high protein binding plate together with an appropriate concentration of compound and [γ-32P]ATP (25 μL/well of a 200 μCi/mL solution in kinase buffer). After incubation for 20 min at 20 ℃, 60 μLl of boiling 2× solubilization buffer containing 10 mM ATP is added to the assay wells to terminate the reactions. Thirty microliters of the samples is removed from the wells, boiled for 5 min, and run on a 7.5% SDS-polyacrylamide gel. The gels are subsequently dried and exposed to Kodak X-AR film. For quantitation, films are scanned using a Molecular Dynamics laser scanner, and the optical density of the major substrate band, enolase p46, is determined. In companion experiments for measuring the activity of compounds against Lck, the assay plate is washed with two wash cycles on a Skatron harvester using 50 mM EDTA, 1 mM ATP. Scintillation fluid (100 μL) is then added to the wells, and 32P incorporation is measured using a micro-β-counter.

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] Hanke JH, et al. J Biol Chem, 1996, 271(2), 695-701.

[2] Tatton L, et al. J Biol Chem, 2003, 278(7), 4847-4853.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02431702 Recruiting Schizophrenia|Psychotic Disorders Janssen Scientific Affairs, LLC July 2015 Phase 4
NCT01515423 Completed Schizophrenia Janssen Research & Development, LLC May 2012 Phase 3

Chemical Information

Download PP1 SDF
Molecular Weight (MW) 281.36
Formula

C16H19N5

CAS No. 172889-26-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms AGL 1872,EI 275
Solubility (25°C) * In vitro DMSO 4 mg/mL (14.21 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
* <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 1H-Pyrazolo[3,4-d]pyrimidin-4-amine, 1-(1,1-dimethylethyl)-3-(4-methylphenyl)-

Customer Product Validation (1)


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Rating
Source J Virol 2011 85(5), 2296-303. PP1 purchased from Selleck
Method Endothelial cell permeability assay
Cell Lines Endothelial cells
Concentrations 10 nM
Incubation Time 15, 30, 60 min
Results In Figure, it assessed the abilities of VEGFR2 and SFK inhibitors to block ANDV-induced permeability at their IC50s from 15 to 60 min after VEGF addition. The Src family inhibitors dasatinib and PP1, which had the lowest IC50s of the kinase inhibitors tested, inhibited ANDV-induced endothelial cell permeability by 40 to 70%.

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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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