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Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile
- Source :
- Journal of medicinal chemistry. 53(16)
- Publication Year :
- 2010
-
Abstract
- A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
- Subjects :
- Models, Molecular
Indoles
Stereochemistry
Aurora B kinase
Stereoisomerism
Antineoplastic Agents
macromolecular substances
Protein Serine-Threonine Kinases
Histones
chemistry.chemical_compound
Structure-Activity Relationship
Aurora kinase
Aurora Kinases
Drug Discovery
Structure–activity relationship
Aurora Kinase B
Humans
Pyrroles
Phosphorylation
Cell Proliferation
Protein-Serine-Threonine Kinases
Kinase
HCT116 Cells
enzymes and coenzymes (carbohydrates)
Biochemistry
chemistry
embryonic structures
Indoline
Molecular Medicine
biological phenomena, cell phenomena, and immunity
Drug Screening Assays, Antitumor
HT29 Cells
HeLa Cells
Protein Binding
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 53
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....499e5e36aadd6bb53dcc723ffcb3b783