PH-797804

Catalog No.S2726 Batch:S272601

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Technical Data

Formula

C22H19BrF2N2O3
Molecular Weight 477.3 CAS No. 586379-66-0
Solubility (25°C)* In vitro DMSO 96 mg/mL (201.13 mM)
Ethanol 7 mg/mL (14.66 mM)
Water 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.)

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Biological Activity

Description PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM in a cell-free assay; 4-fold more selective versus p38β and does not inhibit JNK2. Phase 2.
Targets
p38α [1]
(Cell-free assay)		 p38β [1]
(Cell-free assay)
26 nM 102 nM
In vitro PH-797804 blocks LPS-induced TNF-α production and p38 kinase activity in the human monocytic U937 cell line, with comparable IC50 of 5.9 nM and 1.1 nM. PH-797804 has no inhibitory effect on either the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells at concentrations up to 1 μM. PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner, with IC50 of 3 nM in primary rat bone marrow cells. [1] IC50 values for PH-797804 against the following targets have been determined to be greater than 200 μM (unless specified): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1, which means the activity of PH-797804 is specific. [2]
In vivo Orally dosing of PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. PH-797804 treatment for 10 days demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Dose-response analysis resulted in ED50 values of 0.07 mg/kg and 0.095 mg/kg in rat and cynomolgus monkeys, respectively. PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner in a human endotoxin challenge model. [1]

Protocol (from reference)

Kinase Assay:

[1]
  • P38 kinase assay

    A resin capture assay method is used to determine the phosphorylation of epidermal growth factor receptor peptide (EGFRP) or GST-c-Jun by p38 kinases. Reactions mixtures contain 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, ATP (at the indicated concentration), 0.05 to 0.3 μCi of [γ-33P]ATP, 0.8 mM dithiothreitol, and either 200 μM EGFRP or 10 μM GST-c-Jun for p38α kinase reactions. The reaction is initiated by the addition of 25 nM p38α kinase to give a final volume of 50 μl. The p38αkinase reactions are incubated at 25 °C for 30 minutes. Under these conditions, the formation of product for both p38αkinase is linear with time. The reaction is stopped, and the unreacted [γ-33P]ATP is removed by the addition of 150 μl of AG 1 × 8 ion exchange resin in 900 mM sodium formate, pH 3.0. Once thoroughly mixed, solutions are allowed to stand for 5 minutes. A 50-μl aliquot of head volume containing the phosphorylated substrate is removed from the mixture and transferred to a 96-well plate. MicroScint-40 scintillation cocktail (150 μL) is added to each well and the radioactivity quantities using a TopCount NXT microplate scintillation and luminescence counter.
Cell Assay:

[1]
  • Cell lines

    Rheumatoid arthritis synovial fibroblast(s)

  • Concentrations

    --

  • Incubation Time

    --

  • Method

    Cell viability is evaluated using the 3-(4,5-dimethylthiazol-2-yl)-) diphenyl tetrazolium bromide assay. Absorbance is measured on an ELISA plate reader with a test wavelength of 570 nm and a reference of 630 nm.
Animal Study:

[1]
  • Animal Models

    LPS-induced chronic inflammation rat model

  • Dosages

    0.001-1 mg/kg

  • Administration

    Oral gavage 4 hours before LPS administration

Customer Product Validation

Data independently produced by , , Dr.Wang from Southern Medical Hospital

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Selleck's PH-797804 has been cited by 47 publications

SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK [ Signal Transduct Target Ther, 2024, 9(1):39] PubMed: 38355690
Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia [ Cell Signal, 2024, 114:111004] PubMed: 38048856
Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma [ Nat Commun, 2023, 14(1):861] PubMed: 36792623
HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation [ Elife, 2023, 12e83159] PubMed: 36961408
HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation [ Cell Biology, 2023, 10.7554/eLife.83159] PubMed: None
Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α [ Cancers (Basel), 2023, 15(3)611] PubMed: 36765568
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9] PubMed: 35868306
Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure [ J Clin Invest, 2022, 132(14)e157780] PubMed: 35838051
P38α MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation [ Proc Natl Acad Sci U S A, 2022, 119(32):e2206000119] PubMed: 35914132
Hyperphosphorylated tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer's disease [ J Neuroinflammation, 2022, 19(1):205] PubMed: 35971179

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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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