Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases.
A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-Rbeta, p60(c)()(-)()(Src)(), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-Rbeta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.
Sun
L
L
SUGEN, Inc., 230 East Grand Avenue, South San Francisco, California 94080-4811, USA. connie-sun@sugen.com
Tran
N
N
Liang
C
C
Hubbard
S
S
Tang
F
F
Lipson
K
K
Schreck
R
R
Zhou
Y
Y
McMahon
G
G
Tang
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1
C411455:3-(2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid; C411456:3-(2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011422:Propionates; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1