Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors.
Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.
Gellibert
Françoise
F
Department of Medicinal Chemistry, GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. fjg23217@gsk.com
Woolven
James
J
Fouchet
Marie-Hélène
MH
Mathews
Neil
N
Goodland
Helen
H
Lovegrove
Victoria
V
Laroze
Alain
A
Nguyen
Van-Loc
VL
Sautet
Stéphane
S
Wang
Ruolan
R
Janson
Cheryl
C
Smith
Ward
W
Krysa
Gaël
G
Boullay
Valérie
V
De Gouville
Anne-Charlotte
AC
Huet
Stéphane
S
Hartley
David
D
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009287:Naphthyridines; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human