Fragment-based approaches to the discovery of kinase inhibitors.
Protein kinases are one of the most important families of drug targets, and aberrant kinase activity has been linked to a large number of disease areas. Although eminently targetable using small molecules, kinases present a number of challenges as drug targets, not least obtaining selectivity across such a large and relatively closely related target family. Fragment-based drug discovery involves screening simple, low-molecular weight compounds to generate initial hits against a target. These hits are then optimized to more potent compounds via medicinal chemistry, usually facilitated by structural biology. Here, we will present a number of recent examples of fragment-based approaches to the discovery of kinase inhibitors, detailing the construction of fragment-screening libraries, the identification and validation of fragment hits, and their optimization into potent and selective lead compounds. The advantages of fragment-based methodologies will be discussed, along with some of the challenges associated with using this route. Finally, we will present a number of key lessons derived both from our own experience running fragment screens against kinases and from a large number of published studies.
Astex Pharmaceuticals, Cambridge, United Kingdom. Electronic address: paul.mortenson@astx.com.
Paul N
PN
Mortenson
Astex Pharmaceuticals, Cambridge, United Kingdom.
Valerio
V
Berdini
Astex Pharmaceuticals, Cambridge, United Kingdom.
Marc
M
O'Reilly
D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D030562:Databases, Protein; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D008956:Models, Chemical; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019151:Peptide Library; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries
D010446:Peptide Fragments; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases
Fragment libraries; Fragment screening; Fragment-based drug design; Fragments; Kinase inhibitors; Structure-based drug design