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4-Anilino-7-alkenylquinoline-3-carbonitriles as potent MEK1 kinase inhibitors
- Source :
- Bioorganicmedicinal chemistry. 16(20)
- Publication Year :
- 2008
-
Abstract
- A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure–activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 μM of 5m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.
- Subjects :
- MAPK/ERK pathway
Clinical Biochemistry
MAP Kinase Kinase 1
Pharmaceutical Science
Mice, Nude
Mitogen-activated protein kinase kinase
Alkenes
Biochemistry
Substrate Specificity
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
LYN
In vivo
Cell Line, Tumor
Neoplasms
Drug Discovery
Nitriles
Animals
Humans
Molecular Biology
Protein Kinase Inhibitors
Aniline Compounds
Molecular Structure
Chemistry
Kinase
Organic Chemistry
Biological activity
Isoquinolines
Xenograft Model Antitumor Assays
In vitro
Enzyme Activation
Molecular Medicine
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 16
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....61453aa498eb019fa03b36bd83ab9b0e