Protein–LigandCrystal Structures Can Guidethe Design of Selective Inhibitors of the FGFR Tyrosine Kinase.
- Resource Type
- Article
- Authors
- Norman, Richard A.; Schott, Anne-Kathrin; Andrews, David M.; Breed, Jason; Foote, Kevin M.; Garner, Andrew P.; Ogg, Derek; Orme, Jonathon P.; Pink, Jennifer H.; Roberts, Karen; Rudge, David A.; Thomas, Andrew P.; Leach, Andrew G.
- Source
- Journal of Medicinal Chemistry. Jun2012, Vol. 55 Issue 11, p5003-5012. 10p.
- Subject
- *PROTEIN-ligand interactions
*CRYSTAL structure
*DRUG design
*FIBROBLAST growth factor receptors
*PROTEIN-tyrosine kinase inhibitors
*ADENOSINE triphosphate
- Language
- ISSN
- 0022-2623
The design of compounds that selectively inhibit a singlekinaseis a significant challenge, particularly for compounds that bind tothe ATP site. We describe here how protein–ligand crystal structureinformation was able both to rationalize observed selectivity andto guide the design of more selective compounds. Inhibition data fromenzyme and cellular screens and the crystal structures of a rangeof ligands tested during the process of identifying selective inhibitorsof FGFR provide a step-by-step illustration of the process. Stericeffects were exploited by increasing the size of ligands in specificregions in such a way as to be tolerated in the primary target andnot in other related kinases. Kinases are an excellent target classto exploit such approaches because of the conserved fold and smallside chain mobility of the active form. [ABSTRACT FROM AUTHOR]