1. Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors
- Author
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Yves Le Merrer, François Radvanyi, Aurélie Jonquoy, Catherine Benoist-Lasselin, Laurent Le Corre, Emilie Mugniery, Anne-Lise Girard, Patricia Busca, Laurence Legeai-Mallet, and Johannes Aubertin
- Subjects
Stereochemistry ,Pyridines ,Mutant ,Triazole ,Biochemistry ,Cell Line ,Small Molecule Libraries ,chemistry.chemical_compound ,Structure-Activity Relationship ,Structure–activity relationship ,Humans ,Physical and Theoretical Chemistry ,Binding site ,Kinase activity ,Protein Kinase Inhibitors ,Binding Sites ,Molecular Structure ,Organic Chemistry ,HEK 293 cells ,Stereoisomerism ,Protein-Tyrosine Kinases ,Triazoles ,In vitro ,Recombinant Proteins ,Pyrimidines ,chemistry ,Drug Design ,Tyrosine kinase - Abstract
A library of pyrido[2,3-d]pyrimidines was designed as inhibitors of FGFR3 tyrosine kinase allowing possible interactions with an unexploited region of the ATP binding-site. This library was built-up with an efficient step of click-chemistry giving easy access to triazole-based compounds bearing a large panel of substituents. Among the 27 analogues synthesized, more than half exhibited 55-89% inhibition of in vitro FGFR3 kinase activity at 2 microM and one (19g) was able to inhibit auto-phosphorylation of mutant FGFR3-K650M in transfected HEK cells.
- Published
- 2010