Trends in kinase selectivity: insights for target class-focused library screening.
A kinome-wide selectivity screen of >20000 compounds with a rich representation of many structural classes has been completed. Analysis of the selectivity patterns for each class shows that a broad spectrum of structural scaffolds can achieve specificity for many kinase families. Kinase selectivity and potency are inversely correlated, a trend that is also found in a large set of kinase functional data. Although selective and nonselective compounds are mostly similar in their physicochemical characteristics, we identify specific features that are present more frequently in compounds that bind to many kinases. Our results support a scaffold-oriented approach for building compound collections to screen kinase targets.
Computer-Assisted Drug Design, Applied Biotechnology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States.
Shana L
SL
Posy
Mark A
MA
Hermsmeier
Wayne
W
Vaccaro
Karl-Heinz
KH
Ott
Gordon
G
Todderud
Jonathan S
JS
Lippy
George L
GL
Trainor
Deborah A
DA
Loughney
Stephen R
SR
Johnson
D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D057166:High-Throughput Screening Assays; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D054852:Small Molecule Libraries; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D010770:Phosphotransferases; D066246:ErbB Receptors; D051941:fms-Like Tyrosine Kinase 3; D051357:Cyclin-Dependent Kinase 2