PH-797804
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MedKoo CAT#: 206022

CAS#: 586379-66-0

Description: PH-797804 is a potent and selectiove inhibitor of p38 mitogen-activated protein (MAP) kinase. PH-797804 reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. PH-797804 may have therapeutic interest for colon cancer treatment.

Chemical Structure

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PH-797804
CAS# 586379-66-0
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206022
Name: PH-797804
CAS#: 586379-66-0
Chemical Formula: C22H19BrF2N2O3
Exact Mass: 476.05
Molecular Weight: 477.300
Elemental Analysis: C, 55.36; H, 4.01; Br, 16.74; F, 7.96; N, 5.87; O, 10.06

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1250 Ready to ship
500mg USD 2650 Ready to ship
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Synonym: PH-797804; PH 797804; PH797804.

IUPAC/Chemical Name: 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide

InChi Key: KCAJXIDMCNPGHZ-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H19BrF2N2O3/c1-12-4-5-14(21(28)26-3)9-18(12)27-13(2)8-19(20(23)22(27)29)30-11-15-6-7-16(24)10-17(15)25/h4-10H,11H2,1-3H3,(H,26,28)

SMILES Code: O=C(NC)C1=CC=C(C)C(N2C(C)=CC(OCC3=CC=C(F)C=C3F)=C(Br)C2=O)=C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: soluble in DMSO

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:         

Biological target: PH-797804 is a ATP-competitive, selective p38α/p38β inhibitor (IC50=26 nM and Ki=5.8 nM for p38α; Ki=40 nM for p38β) and does not inhibit JNK2.
In vitro activity: The aim of this study was to investigate the effect of OGD in young and aged primary rat astrocyte cultures and to analyze the expression and effect of p38MAPK in these cultures. For this, this study cultured young and aged astrocytes with PH-797804, MAPK14 (p38α) inhibitor, the most abundant isoform of p38MAPK in the brain, to define changes in supporting and protective properties of astrocytes that can be critical for survival of brain cells. For assays with P38MAPK inhibitor, astrocytes were treated with 2 μM PH-797804 (Selleckchem) added to the medium when seeded and included in every medium change. the addition of PH797804 to aged astrocyte cultures lowered levels of P-P38MAPK and Mapk14 (p38alpha) gene expression by 50% after OGD and after reperfusion in comparison to control cells. Analysis of TNFα, GFAP and P-p38MAPK protein expression after OGD revealed that there was a reduction of all these proteins in aged astrocytes treated with PH-797804 after OGD. In the results, the inactivation of p38α in aged astrocyte cultures treated by PH-797804 attenuated astroglial activation and inflammation that occur after OGD. It was also found that PH-797804 treatment in aged astrocytes can prevent OGD-induced changes of growth factors igf and ngf, of the free radical clearance factors sod2 and gclc, and of the glutamate metabolism system gs that were increased after OGD. Reference : Aging (Albany NY). 2021 Mar 15; 13(5): 6346–6358. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993689/
In vivo activity: To investigate the role of p38 MAPK signaling in the PDXs from CRC, the inhibitor PH797804 was used. This chemical compound effectively inhibits the p38α and p38β MAPKs, without affecting other MAPKs such as ERK1/2 and JNK, and it is used in clinical trials for inflammatory diseases. Tumors in PDXs were allowed to grow up to a measurable size (150-200 mm3) and then mice were randomized into two groups, which received either PH797804 or vehicle. Models CCR-010 and CCR-024 showed a decrease in tumor size when treated with PH797804 during the first 5-7 days. Then, tumors started to grow again although significantly slower than the vehicle treated tumors. These two models were treated for 10 days (Figure2). Model CCR-038 showed a more pronounced growth inhibition during all the treatment with PH797804. Due to the different response observed, in this case the treatment was extended until day 16 to confirm that tumor growth inhibition was maintained (Figure2). Therefore, tumor growth was significantly reduced in the PH797804-treated mice for the three PDX models of CRC, although there were slight differences in the response of each model. Reference: Oncotarget. 2015 Apr 20; 6(11): 8539–8551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496165/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 14.0 29.30

Preparing Stock Solutions

The following data is based on the product molecular weight 477.30 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Revuelta M, Elicegui A, Scheuer T, Endesfelder S, Bührer C, Moreno-Cugnon L, Matheu A, Schmitz T. In vitro P38MAPK inhibition in aged astrocytes decreases reactive astrocytes, inflammation and increases nutritive capacity after oxygen-glucose deprivation. Aging (Albany NY). 2021 Feb 9;13(5):6346-6358. doi: 10.18632/aging.202651. Epub 2021 Feb 9. PMID: 33563843; PMCID: PMC7993689. 2. Moreno-Cugnon L, Arrizabalaga O, Llarena I, Matheu A. Elevated p38MAPK activity promotes neural stem cell aging. Aging (Albany NY). 2020 Apr 3;12(7):6030-6036. doi: 10.18632/aging.102994. Epub 2020 Apr 3. PMID: 32243258; PMCID: PMC7185101. 3. Hope HR, Anderson GD, Burnette BL, Compton RP, Devraj RV, Hirsch JL, Keith RH, Li X, Mbalaviele G, Messing DM, Saabye MJ, Schindler JF, Selness SR, Stillwell LI, Webb EG, Zhang J, Monahan JB. Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther. 2009 Dec;331(3):882-95. doi: 10.1124/jpet.109.158329. Epub 2009 Aug 31. PMID: 19720877. 4. Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors. Oncotarget. 2015 Apr 20;6(11):8539-51. doi: 10.18632/oncotarget.3816. PMID: 25890501; PMCID: PMC4496165.
In vitro protocol: 1. Revuelta M, Elicegui A, Scheuer T, Endesfelder S, Bührer C, Moreno-Cugnon L, Matheu A, Schmitz T. In vitro P38MAPK inhibition in aged astrocytes decreases reactive astrocytes, inflammation and increases nutritive capacity after oxygen-glucose deprivation. Aging (Albany NY). 2021 Feb 9;13(5):6346-6358. doi: 10.18632/aging.202651. Epub 2021 Feb 9. PMID: 33563843; PMCID: PMC7993689. 2. Moreno-Cugnon L, Arrizabalaga O, Llarena I, Matheu A. Elevated p38MAPK activity promotes neural stem cell aging. Aging (Albany NY). 2020 Apr 3;12(7):6030-6036. doi: 10.18632/aging.102994. Epub 2020 Apr 3. PMID: 32243258; PMCID: PMC7185101.
In vivo protocol: 1. Hope HR, Anderson GD, Burnette BL, Compton RP, Devraj RV, Hirsch JL, Keith RH, Li X, Mbalaviele G, Messing DM, Saabye MJ, Schindler JF, Selness SR, Stillwell LI, Webb EG, Zhang J, Monahan JB. Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther. 2009 Dec;331(3):882-95. doi: 10.1124/jpet.109.158329. Epub 2009 Aug 31. PMID: 19720877. 2. Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors. Oncotarget. 2015 Apr 20;6(11):8539-51. doi: 10.18632/oncotarget.3816. PMID: 25890501; PMCID: PMC4496165.

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1: Singh D, Siew L, Christensen J, Plumb J, Clarke GW, Greenaway S, Perros-Huguet C, Clarke N, Kilty I, Tan L. Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects. Eur J Clin Pharmacol. 2015 Oct;71(10):1175-84. doi: 10.1007/s00228-015-1920-1. Epub 2015 Aug 13. PubMed PMID: 26265232; PubMed Central PMCID: PMC4564450.

2: Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors. Oncotarget. 2015 Apr 20;6(11):8539-51. PubMed PMID: 25890501; PubMed Central PMCID: PMC4496165.

3: Norman P. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2015 Mar;24(3):383-92. doi: 10.1517/13543784.2015.1006358. Epub 2015 Jan 20. Review. PubMed PMID: 25599809.

4: Singh D. P38 inhibition in COPD; cautious optimism. Thorax. 2013 Aug;68(8):705-6. doi: 10.1136/thoraxjnl-2013-203498. Epub 2013 Apr 23. PubMed PMID: 23611882.

5: MacNee W, Allan RJ, Jones I, De Salvo MC, Tan LF. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax. 2013 Aug;68(8):738-45. doi: 10.1136/thoraxjnl-2012-202744. Epub 2013 Mar 28. PubMed PMID: 23539534.

6: Xing L, Devadas B, Devraj RV, Selness SR, Shieh H, Walker JK, Mao M, Messing D, Samas B, Yang JZ, Anderson GD, Webb EG, Monahan JB. Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemMedChem. 2012 Feb 6;7(2):273-80. doi: 10.1002/cmdc.201100439. Epub 2011 Dec 15. PubMed PMID: 22174080.

7: Selness SR, Devraj RV, Devadas B, Walker JK, Boehm TL, Durley RC, Shieh H, Xing L, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R, Messing D, Yang J, Mao MK, Yalamanchili G, Vonder Embse R, Hirsch J, Saabye M, Bonar S, Webb E, Anderson G, Monahan JB. Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase. Bioorg Med Chem Lett. 2011 Jul 1;21(13):4066-71. doi: 10.1016/j.bmcl.2011.04.121. Epub 2011 May 11. PubMed PMID: 21641211.

8: Hope HR, Anderson GD, Burnette BL, Compton RP, Devraj RV, Hirsch JL, Keith RH, Li X, Mbalaviele G, Messing DM, Saabye MJ, Schindler JF, Selness SR, Stillwell LI, Webb EG, Zhang J, Monahan JB. Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther. 2009 Dec;331(3):882-95. doi: 10.1124/jpet.109.158329. Epub 2009 Aug 31. PubMed PMID: 19720877.

9: Xing L, Shieh HS, Selness SR, Devraj RV, Walker JK, Devadas B, Hope HR, Compton RP, Schindler JF, Hirsch JL, Benson AG, Kurumbail RG, Stegeman RA, Williams JM, Broadus RM, Walden Z, Monahan JB. Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804. Biochemistry. 2009 Jul 14;48(27):6402-11. doi: 10.1021/bi900655f. PubMed PMID: 19496616.