1. Kinase array design, back to front: Biaryl amides
- Author
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Paul Bamborough, Ian Robert Baldwin, Jo Quinn, Don O. Somers, Christopher J. Mooney, Claudine Haslam, Shila Patel, Suchete S. Hunjan, and Tim Longstaff
- Subjects
Models, Molecular ,Purine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,Mitogen-Activated Protein Kinase 14 ,Heterocyclic Compounds, 1-Ring ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Adenosine Triphosphate ,Amide ,Drug Discovery ,Animals ,Combinatorial Chemistry Techniques ,Structure–activity relationship ,Transferase ,Protein Kinase Inhibitors ,Molecular Biology ,Molecular Structure ,biology ,Chemistry ,Kinase ,Organic Chemistry ,Amides ,Rats ,Mitogen-activated protein kinase ,biology.protein ,Molecular Medicine ,Signal transduction - Abstract
New kinase inhibitors can be found by synthesis of targeted arrays of compounds designed using system-based knowledge as well as through screening focused or diverse compounds. Most array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38alpha and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties.
- Published
- 2008