Pyrimidinylimidazole inhibitors of CSBP/P38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

Adams, Jerry L.; Boehm, Jeffrey C.; Kassis, Shouki; Gorycki, Peter D.; Webb, Edward F.; Hall, Ralph F.; Sorenson, Margaret E.; Lee, John C.; Ayrton, Andrew D.; Griswold, Don E.; Gallagher, Timothy F.

doi:10.1016/s0960-894x(98)00549-6

Cited by 123 publications

(72 citation statements)

References 13 publications

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“…For instance, SB203580 has been shown to exhibit inhibitory activity against PKB via direct inhibition of phosphoinositide-dependent kinase 1 (PDK1) but not via inhibition of PI3K at moderately high drug concentrations (Ͼ1-3 M) (118). Similarly, SB203580 has been shown to affect the activity of the hepatic cytochrome P450 enzymes (119). This activity is explained by the fact that pyridine and imidazole components of the SB203580 compound are ligands for the heme iron of cytochrome P450 (120).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic and Transcriptional Analysis of the Response to the p38 Mitogen-activated Protein Kinase Inhibitor SB203580 in Transformed Follicular Lymphoma Cells

Lin

Crockett

Jenson

et al. 2004

Molecular & Cellular Proteomics

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The p38 mitogen-activated protein kinase (MAPK) is a key mediator of stress, extracellular-, growth factor-, and cytokine-induced signaling, and has been implicated in the development of cancer. Our previous work showed evidence for p38 MAPK activation in a subset of transformed follicular lymphomas (Elenitoba-Johnson et al. An important aim of functional genomic research is to globally identify and quantify specific proteomic and/or transcriptomic changes that are associated with physiologic or diseased states, thus enabling the elucidation of genes/proteins and signaling pathways that are associated with the phenotypic expression of a particular cellular state. The currently available microarray technologies permit the quantification of tens of thousands of gene transcripts and have been largely successful in demonstrating the global transcriptional changes accompanying the transition between cellular quiescence and activation, or during transition from normal to pathologic states (1-7). Proteomics, on the other hand, allows identification and quantification of up to a few thousand proteins, limited by the currently available technologies and the complex nature of the proteome especially in higher eukaryotes and mammalian cell systems. While the most widely used proteomics approach is the two-dimensional (2-D) 1 gel-based method followed by MS (8 -10), the recent development of multidimensional liquid chromatographic methods combined with MS/MS (LC-LC-MS/MS) has permitted sensitive detection of low-abundance proteins, membrane proteins and proteins with extreme pI (11-15). The ability to perform global quantitative proteomics has been significantly enhanced by the advent of the ICAT-based technology that is efficient in simplifying the proteome, and in combination with threedimensional 3-D LC-MS/MS permits detection and quantifiFrom the ‡Associated Regional and University Pathologists (ARUP)

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Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic and Transcriptional Analysis of the Response to the p38 Mitogen-activated Protein Kinase Inhibitor SB203580 in Transformed Follicular Lymphoma Cells

Lin

Crockett

Jenson

et al. 2004

Molecular & Cellular Proteomics

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“…The 2,6-dichloro substitution emerged as optimal, as indicated by compound 21, which also demonstrated corresponding inhibition of IL-1β and TNFR release from lipopolysaccharide (LPS) treated human peripheral blood mononuclear cells (PBMCs). For other 2,6-disubstituted systems examined (19,20), potency was approximately 10-fold weaker than that of 21.…”

Section: à18mentioning

confidence: 93%

“…19 However, it has been previously reported that the presence of the pyridyl moiety in 1 and 2 leads to significant inhibition of hepatic cytochrome p450 isozymes in vitro, 20 rendering these compounds unsuitable for development in the treatment of chronic disease.…”

Section: à18mentioning

confidence: 99%

The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

Duffy

Harrington²,

Salituro³

et al. 2011

ACS Med. Chem. Lett.

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“…However, they did not enter the clinic due to their effects on P450 enzymes and associated liver safety issues. 33 Subsequently, even more selective inhibitors have been discovered and have progressed into clinical trials. 34 Unfortunately, none of these has proved to show efficacy in rheumatoid arthritis for reasons that are not entirely clear, and most have shown some evidence for common adverse events.…”

Section: Protein Kinases As Drug Targetsmentioning

confidence: 99%

Perspective on the Discovery and Scientific Impact of p38 MAP Kinase

Young

2013

SLAS Discovery

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It has now been almost 20 years since the discovery of p38 MAP kinase and its role in inflammatory cytokine synthesis through reverse pharmacology and its subsequent exploration as a potential target for autoimmune and other diseases. At the time of its discovery, the use of cell-based phenotypic screens to identify new molecular targets was at its infancy, and while p38 MAP kinase was not the first target to be identified this way, it provides a useful model for reviewing the pros and cons of this approach and the subsequent impact it can have on discovering new medicines.

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Pyrimidinylimidazole inhibitors of CSBP/P38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

Cited by 123 publications

References 13 publications

Quantitative Proteomic and Transcriptional Analysis of the Response to the p38 Mitogen-activated Protein Kinase Inhibitor SB203580 in Transformed Follicular Lymphoma Cells

Quantitative Proteomic and Transcriptional Analysis of the Response to the p38 Mitogen-activated Protein Kinase Inhibitor SB203580 in Transformed Follicular Lymphoma Cells

The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

Perspective on the Discovery and Scientific Impact of p38 MAP Kinase

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