An amino-indazole scaffold with spectrum selective kinase inhibition of FLT3, PDGFRα and kit.
Here we describe the synthesis and characterization of a number of 3-amino-1H-indazol-6-yl-benzamides that were designed to target the 'DFG-out' conformation of the kinase activation loop. Several compounds such as 4 and 11 exhibit single-digit nanomolar EC(50)s against FLT3, c-Kit and the gatekeeper T674M mutant of PDGFRα.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Xianming
X
Deng
Wenjun
W
Zhou
Ellen
E
Weisberg
Jinhua
J
Wang
Jianming
J
Zhang
Takaaki
T
Sasaki
Erik
E
Nelson
James D
JD
Griffin
Pasi A
PA
Jänne
Nathanael S
NS
Gray
D000818:Animals; D002460:Cell Line; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051941:fms-Like Tyrosine Kinase 3