The discovery of substituted 4-(3-hydroxyanilino)-quinolines as potent RET kinase inhibitors.
Substituted 4-(3-hydroxyanilino)-quinoline compounds, initially identified as small-molecule inhibitors of src family kinases, have been evaluated as potential inhibitors of RET kinase. Three compounds, 38, 31, and 40, had K(i)'s of 3, 25, and 50 nM in an in vitro kinase assay; while a cell based kinase assay showed K(i)'s of 300, 100, and 45 nM, respectively. These compounds represent potential new leads for the treatment of medullary and papillary thyroid cancer.
Graham Robinett
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R
GlaxoSmithKline, Molecular Discovery Research Chemistry, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Freemerman
Alex J
AJ
Skinner
Michael A
MA
Shewchuk
Lisa
L
Lackey
Karen
K
D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human