Limits...
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.

Gandin V, Ferrarese A, Dalla Via M, Marzano C, Chilin A, Marzaro G - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).

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.

No MeSH data available.


Related in: MedlinePlus

Results of primary screening of compounds against kinases.The heat map displays the results of the primary screening in terms of POC values for each pair of kinase/ligand. The lower the POC (white to red boxes), the tighter the binding. Compounds are listed according to Fig. 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4645160&req=5

f4: Results of primary screening of compounds against kinases.The heat map displays the results of the primary screening in terms of POC values for each pair of kinase/ligand. The lower the POC (white to red boxes), the tighter the binding. Compounds are listed according to Fig. 2.

Mentions: The compounds were tested at high concentration (10 μM), in order to highlight not only the main target but also the off-targets. The results of the preliminary screening are reported as heat map (Fig. 4; see also Table S4 for all the measured values), in which the compounds are grouped on the basis of the 6 or 5 substituent at the pyrimidine ring.


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.

Gandin V, Ferrarese A, Dalla Via M, Marzano C, Chilin A, Marzaro G - Sci Rep (2015)

Results of primary screening of compounds against kinases.The heat map displays the results of the primary screening in terms of POC values for each pair of kinase/ligand. The lower the POC (white to red boxes), the tighter the binding. Compounds are listed according to Fig. 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645160&req=5

f4: Results of primary screening of compounds against kinases.The heat map displays the results of the primary screening in terms of POC values for each pair of kinase/ligand. The lower the POC (white to red boxes), the tighter the binding. Compounds are listed according to Fig. 2.
Mentions: The compounds were tested at high concentration (10 μM), in order to highlight not only the main target but also the off-targets. The results of the preliminary screening are reported as heat map (Fig. 4; see also Table S4 for all the measured values), in which the compounds are grouped on the basis of the 6 or 5 substituent at the pyrimidine ring.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).

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.

No MeSH data available.


Related in: MedlinePlus