Kinomics: characterizing the therapeutically validated kinase space.
The annotation and visualization of medicinally relevant kinase space revealed that kinase inhibitors in the clinic are, on average, of higher molecular weight and more lipophilic than all other clinically investigated drugs. Tyrosine kinases from the vascular endothelial growth factor and epidermal growth factor receptor families are the most pursued targets. Furthermore, oncological indications account for 75% of all kinase-related clinical interest. In addition, analysis of the similarity between kinase targets with respect to sequence, selectivity and structure has revealed that kinases with > or =60% sequence identity are most likely to be inhibited by the same classes of compounds and have similar ATP-binding sites. The identification of this threshold, together with the widely accepted representation of the sequence-based kinase space, is expanding our understanding of the clinical and structural space of the kinome.
Vieth
Michal
M
Discovery Chemistry Research, Lilly Research Laboratories, Lilly Corporate Center, DC 1513, Indianapolis, IN 46285, USA. m.vieth@lilly.com
Sutherland
Jeffrey J
JJ
Robertson
Daniel H
DH
Campbell
Robert M
RM
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000737:chemistry*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases