Abstract
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.
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors*
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Binding Sites
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Crystallography, X-Ray
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Humans
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Inhibitory Concentration 50
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacology*
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Phosphorylation / drug effects
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Protein Binding
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Protein Serine-Threonine Kinases
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Pyrazoles / chemical synthesis
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Pyrazoles / pharmacology
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Naphthyridines
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Pyrazoles
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Receptors, Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human