Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: rational design and kinase selectivity profile of cell potent type II inhibitors
| Autor: | Steve Wenglowsky, Hillary L. Sturgis, Walter C. Voegtli, Joachim Rudolph, David A. Moreno, Susan L. Gloor, Tyler Risom, Ellen R. Laird, Li Ren |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Proto-Oncogene Proteins B-raf Stereochemistry Pyridines Clinical Biochemistry Cell Pharmaceutical Science Crystallography X-Ray Biochemistry Mice Structure-Activity Relationship Drug Stability Microsomes Drug Discovery Pyrazolopyridine medicine Animals Humans Molecular Biology Protein Kinase Inhibitors Dose-Response Relationship Drug Molecular Structure Kinase Chemistry Organic Chemistry Rational design Rats medicine.anatomical_structure Drug Design Cyclin-dependent kinase complex Molecular Medicine Pyrazoles Selectivity Linker |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(19) |
| ISSN: | 1464-3405 |
| Popis: | Cell potent inhibitors of B-Raf V600E that bind to the kinase in the DFG-out conformation are reported. These compounds utilize the hinge-binding group and lipophilic linker from a previously disclosed series of B-Raf V600E inhibitors that bind to the kinase in an atypical DFG-in, αC-helix-out conformation. This new series demonstrates that DFG-out kinase inhibitors can be rationally designed from related inhibitors which utilize an unconventional binding mode. Kinase selectivity profiles are compared. The pattern of kinase selectivity was found to be determined by the feature of the inhibitor which extends into the back pocket of the kinase and leads to the kinase conformation, rather than by the hinge-binding group or other minor modifications. |
| Databáze: | OpenAIRE |
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