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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

Structure of kinases and of designed compounds.(a) Main element in kinase structure. (b) Binding of AMP-ANP (PDB ID: 2GS7). (c) Schematic representation of binding of ATP and features of the ATP binding pocket. (d) Detail of binding of a kinase inhibitor (erlotinib; PDB ID: 1M17). (e) Schematic representation of binding of inhibitor (erlotinib) with respect to the features of the ATP binding pocket. Image partially readapted from ref. 22. (f) General structures of designed compounds and their structural relationship with 4-anilinoquinazolines. (g) Supposed binding mode of designed compounds in the ATP binding pocket.
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f1: Structure of kinases and of designed compounds.(a) Main element in kinase structure. (b) Binding of AMP-ANP (PDB ID: 2GS7). (c) Schematic representation of binding of ATP and features of the ATP binding pocket. (d) Detail of binding of a kinase inhibitor (erlotinib; PDB ID: 1M17). (e) Schematic representation of binding of inhibitor (erlotinib) with respect to the features of the ATP binding pocket. Image partially readapted from ref. 22. (f) General structures of designed compounds and their structural relationship with 4-anilinoquinazolines. (g) Supposed binding mode of designed compounds in the ATP binding pocket.

Mentions: The ATP pocket is delimited by the hinge region (containing also the gatekeeper residue), the P-loop, the C-helix and the activation loop (containing the highly conserved DFG motif; Fig. 1a). The ATP binding pocket is constituted by the adenine pocket, the hydrophilic ribose pocket and two hydrophobic regions (Fig. 1b,c). Accordingly, TKIs are commonly constituted by i) a nitrogen containing heterocycle able to form an H-bond with the hinge region; ii) an hydrophobic moiety interacting with the hydrophobic region I of the kinase; iii) a spacer between the heterocycle and the hydrophobic moiety (Fig. 1d,e)1522.


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)

Structure of kinases and of designed compounds.(a) Main element in kinase structure. (b) Binding of AMP-ANP (PDB ID: 2GS7). (c) Schematic representation of binding of ATP and features of the ATP binding pocket. (d) Detail of binding of a kinase inhibitor (erlotinib; PDB ID: 1M17). (e) Schematic representation of binding of inhibitor (erlotinib) with respect to the features of the ATP binding pocket. Image partially readapted from ref. 22. (f) General structures of designed compounds and their structural relationship with 4-anilinoquinazolines. (g) Supposed binding mode of designed compounds in the ATP binding pocket.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Structure of kinases and of designed compounds.(a) Main element in kinase structure. (b) Binding of AMP-ANP (PDB ID: 2GS7). (c) Schematic representation of binding of ATP and features of the ATP binding pocket. (d) Detail of binding of a kinase inhibitor (erlotinib; PDB ID: 1M17). (e) Schematic representation of binding of inhibitor (erlotinib) with respect to the features of the ATP binding pocket. Image partially readapted from ref. 22. (f) General structures of designed compounds and their structural relationship with 4-anilinoquinazolines. (g) Supposed binding mode of designed compounds in the ATP binding pocket.
Mentions: The ATP pocket is delimited by the hinge region (containing also the gatekeeper residue), the P-loop, the C-helix and the activation loop (containing the highly conserved DFG motif; Fig. 1a). The ATP binding pocket is constituted by the adenine pocket, the hydrophilic ribose pocket and two hydrophobic regions (Fig. 1b,c). Accordingly, TKIs are commonly constituted by i) a nitrogen containing heterocycle able to form an H-bond with the hinge region; ii) an hydrophobic moiety interacting with the hydrophobic region I of the kinase; iii) a spacer between the heterocycle and the hydrophobic moiety (Fig. 1d,e)1522.

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