Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors.
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.
Le Corre
Laurent
L
Université Paris Descartes, UMR 8601-CNRS, 45 rue des Saints-Pères, 75006 Paris, France.
Girard
Anne-Lise
AL
Aubertin
Johannes
J
Radvanyi
François
F
Benoist-Lasselin
Catherine
C
Jonquoy
Aurélie
A
Mugniery
Emilie
E
Legeai-Mallet
Laurence
L
Busca
Patricia
P
Le Merrer
Yves
Y
D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
C573238:1-tert-butyl-3-(6-(3,5-dimethoxyphenyl)-2-((1-((1-methylpiperidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methylamino)pyrido(2,3-d)pyrimidin-7-yl)urea; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014230:Triazoles; D011505:Protein-Tyrosine Kinases