Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors.
The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases.
Tang
Jun
J
GlaxoSmithKline, Research Triangle Park, NC 27709, USA. jun.tang@gsk.com
Hamajima
Toshihiro
T
Nakano
Masato
M
Sato
Hideyuki
H
Dickerson
Scott H
SH
Lackey
Karen E
KE
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D008956:Models, Chemical; D015394:Molecular Structure; D010770:Phosphotransferases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D007211:Indoles; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases; D048493:Proto-Oncogene Proteins B-raf