A quantitative analysis of kinase inhibitor selectivity.
Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
Karaman
Mazen W
MW
Ambit Biosciences, 4215 Sorrento Valley Blvd., San Diego, California 92121, USA.
Herrgard
Sanna
S
Treiber
Daniel K
DK
Gallant
Paul
P
Atteridge
Corey E
CE
Campbell
Brian T
BT
Chan
Katrina W
KW
Ciceri
Pietro
P
Davis
Mindy I
MI
Edeen
Philip T
PT
Faraoni
Raffaella
R
Floyd
Mark
M
Hunt
Jeremy P
JP
Lockhart
Daniel J
DJ
Milanov
Zdravko V
ZV
Morrison
Michael J
MJ
Pallares
Gabriel
G
Patel
Hitesh K
HK
Pritchard
Stephanie
S
Wodicka
Lisa M
LM
Zarrinkar
Patrick P
PP
D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D020543:Proteome / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D020543:Proteome; D010770:Phosphotransferases