PH-797804 | CAS#586379-66-0 | p38MAP inhibitor

MedKoo Cat#: 206022 | Name: PH-797804

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

PH-797804

CAS#586379-66-0

Theoretical Analysis

MedKoo Cat#: 206022

Name: PH-797804

CAS#: 586379-66-0

Chemical Formula: C22H19BrF2N2O3

Exact Mass: 476.0547

Molecular Weight: 477.30

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
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship

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Related CAS #

No Data

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C8R05B17

QC Data

View QC data: current batch, Lot#C8R05B17

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	14.0	29.30

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

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.

1: Faist A, Schloer S, Mecate-Zambrano A, Janowski J, Schreiber A, Boergeling Y, Conrad BCG, Kumar S, Toebben L, Schughart K, Baumgardt M, Kessler M, Hoenzke K, Hocke A, Trautmann M, Hartmann W, Kato H, Rescher U, Christersson A, Kuehn J, Mellmann A, Wolff T, Kuempers P, Rovas A, Wiewrodt R, Wiebe K, Barth P, Ludwig S, Brunotte L. Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier. Antiviral Res. 2023 Jan;209:105475. doi: 10.1016/j.antiviral.2022.105475. Epub 2022 Nov 21. PMID: 36423831; PMCID: PMC9677559. 2: Maruyama H, Sakai S, Ieda M. Endothelin-1 alters BMP signaling to promote proliferation of pulmonary artery smooth muscle cells. Can J Physiol Pharmacol. 2022 Oct 1;100(10):1018-1027. doi: 10.1139/cjpp-2022-0104. Epub 2022 Aug 29. PMID: 36037530. 3: Guo YN, Cui SJ, Tian YJ, Zhao NR, Zhang YD, Gan YH, Zhou YH, Wang XD. Chondrocyte apoptosis in temporomandibular joint osteoarthritis promotes bone resorption by enhancing chemotaxis of osteoclast precursors. Osteoarthritis Cartilage. 2022 Aug;30(8):1140-1153. doi: 10.1016/j.joca.2022.04.002. Epub 2022 May 2. PMID: 35513247. 4: 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. 5: Donoghue C, Cubillos-Rojas M, Gutierrez-Prat N, Sanchez-Zarzalejo C, Verdaguer X, Riera A, Nebreda AR. Optimal linker length for small molecule PROTACs that selectively target p38α and p38β for degradation. Eur J Med Chem. 2020 Sep 1;201:112451. doi: 10.1016/j.ejmech.2020.112451. Epub 2020 Jun 18. PMID: 32634680. 6: 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. 7: Qu J, Zhou C, Hao N, Chen G, Xia S, Wei H, Fang L. Development of a validated UPLC-MS/MS method for quantification of p38 MAPK inhibitor PH-797804: Application to a pharmacokinetic study in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Dec 15;1134-1135:121877. doi: 10.1016/j.jchromb.2019.121877. Epub 2019 Nov 14. PMID: 31785533. 8: Casadomé-Perales Á, Matteis L, Alleva M, Infantes-Rodríguez C, Palomares- Pérez I, Saito T, Saido TC, Esteban JA, Nebreda AR, de la Fuente JM, Dotti CG. Inhibition of p38 MAPK in the brain through nasal administration of p38 inhibitor loaded in chitosan nanocapsules. Nanomedicine (Lond). 2019 Sep;14(18):2409-2422. doi: 10.2217/nnm-2018-0496. Epub 2019 Aug 28. PMID: 31456488. 9: Chaudhary O, Narayan V, Lelis F, Linz B, Watkins M, Veazey R, Aldovini A. Inhibition of p38 MAPK in combination with ART reduces SIV-induced immune activation and provides additional protection from immune system deterioration. PLoS Pathog. 2018 Aug 30;14(8):e1007268. doi: 10.1371/journal.ppat.1007268. PMID: 30161247; PMCID: PMC6135519. 10: Cánovas B, Igea A, Sartori AA, Gomis RR, Paull TT, Isoda M, Pérez-Montoyo H, Serra V, González-Suárez E, Stracker TH, Nebreda AR. Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells. Cancer Cell. 2018 Jun 11;33(6):1094-1110.e8. doi: 10.1016/j.ccell.2018.04.010. Epub 2018 May 24. PMID: 29805078. 11: Schönrogge M, Kerndl H, Zhang X, Kumstel S, Vollmar B, Zechner D. α-cyano-4-hydroxycinnamate impairs pancreatic cancer cells by stimulating the p38 signaling pathway. Cell Signal. 2018 Jul;47:101-108. doi: 10.1016/j.cellsig.2018.03.015. Epub 2018 Mar 30. PMID: 29609037. 12: Maudens P, Seemayer CA, Pfefferlé F, Jordan O, Allémann E. Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis. J Control Release. 2018 Apr 28;276:102-112. doi: 10.1016/j.jconrel.2018.03.007. Epub 2018 Mar 7. PMID: 29524442. 13: Jones DS, Jenney AP, Joughin BA, Sorger PK, Lauffenburger DA. Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition. Sci Signal. 2018 Mar 6;11(520):eaal1601. doi: 10.1126/scisignal.aal1601. PMID: 29511118; PMCID: PMC5978689. 14: Hashem HM, Mahrouse MA. In vitro metabolism study of a novel P38 kinase inhibitor: in silico predictions, structure elucidation using MS/MS-I. Future Med Chem. 2018 Jan;10(2):201-220. doi: 10.4155/fmc-2017-0126. Epub 2017 Dec 14. PMID: 29239233. 15: Sulen A, Gullaksen SE, Bader L, McClymont DW, Skavland J, Gavasso S, Gjertsen BT. Signaling effects of sodium hydrosulfide in healthy donor peripheral blood mononuclear cells. Pharmacol Res. 2016 Nov;113(Pt A):216-227. doi: 10.1016/j.phrs.2016.08.018. Epub 2016 Aug 16. PMID: 27543462. 16: 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. PMID: 26265232; PMCID: PMC4564450. 17: 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. 18: 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. PMID: 25599809. 19: 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. PMID: 23611882. 20: 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. PMID: 23539534.