Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily.

Abstract	Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi-tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.
Authors	Valentina Gandin, Alessandro Ferrarese, Martina Dalla Via, Cristina Marzano, Adriana Chilin, Giovanni Marzaro
Journal	Scientific reports (Sci Rep) Vol. 5 Pg. 16750 (Nov 16 2015) ISSN: 2045-2322 [Electronic] England
PMID	26568452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Protein Kinase Inhibitors Pyrimidines Urea Receptor Protein-Tyrosine Kinases
Topics	Animals Binding Sites Carcinoma, Lewis Lung (drug therapy, pathology) Cell Line, Tumor Cell Proliferation (drug effects) Cell Survival (drug effects) HEK293 Cells Humans Mice Mice, Inbred C57BL Molecular Docking Simulation Protein Kinase Inhibitors (chemical synthesis, chemistry, therapeutic use) Protein Structure, Tertiary Pyrimidines (chemical synthesis, chemistry, pharmacology) Receptor Protein-Tyrosine Kinases Structure-Activity Relationship Transplantation, Heterologous Urea (analogs & derivatives, chemical synthesis, pharmacology)

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