title: 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.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ferrarese
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Martina
authors.initials: M
authors.lastname: Dalla Via
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marzaro
mesh_terms: D000818:Animals; D001665:Binding Sites; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014508:Urea; D020794:Receptor Protein-Tyrosine Kinases