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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

Binding mode study on compounds 19 and 27.(a) Sequences of hinge, DGF and hydrophobic pocket I regions of the ATP binding pocket for class III RTKs. Black (or red) characters indicate amino acids that place the side chain inside the ATP-pocket; grey characters indicate the amino acids that place the side chain outside the ATP-pocket. Amino acids that place the side chain inside the ATP-pocket and that differ between the five kinases are highlighted in red. The gatekeeper residue number is also reported. (b–f) Results of docking simulations: (b) Potential binding mode of 19 (gray stick) with KIT (green sticks); (c) Potential binding mode of 27 (blue stick) with KIT (green sticks); (d) Potential binding mode of 19 (yellow sticks) with CSF1R (pink sticks); (e) Potential binding mode of 19 (light pink sticks) with FLT3 (cyan sticks); (f) Potential binding mode of 27 (blue sticks) with KIT (green sticks and green cartoons), in context with the ATP binding site features. The 6-phenyl moiety of compound 27 is placed in the hydrophobic pocket II, whereas the hydrophilic function (i.e. the morpholine ring) is placed in the ribose pocket. (g,h) Details of docking simulations for compound 19 (yellow sticks) in KIT (blue sticks, panel (g)) and CSF1R (green sticks, panel (h)). Compound 19, KITC809 and CSF1RG795 are depicted as transparent surfaces. The gatekeeper residues (KITT670 and CSF1RT663) as well as other protein residues are depicted as sticks in order to allow a better comprehension of the compound binding modes.
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f8: Binding mode study on compounds 19 and 27.(a) Sequences of hinge, DGF and hydrophobic pocket I regions of the ATP binding pocket for class III RTKs. Black (or red) characters indicate amino acids that place the side chain inside the ATP-pocket; grey characters indicate the amino acids that place the side chain outside the ATP-pocket. Amino acids that place the side chain inside the ATP-pocket and that differ between the five kinases are highlighted in red. The gatekeeper residue number is also reported. (b–f) Results of docking simulations: (b) Potential binding mode of 19 (gray stick) with KIT (green sticks); (c) Potential binding mode of 27 (blue stick) with KIT (green sticks); (d) Potential binding mode of 19 (yellow sticks) with CSF1R (pink sticks); (e) Potential binding mode of 19 (light pink sticks) with FLT3 (cyan sticks); (f) Potential binding mode of 27 (blue sticks) with KIT (green sticks and green cartoons), in context with the ATP binding site features. The 6-phenyl moiety of compound 27 is placed in the hydrophobic pocket II, whereas the hydrophilic function (i.e. the morpholine ring) is placed in the ribose pocket. (g,h) Details of docking simulations for compound 19 (yellow sticks) in KIT (blue sticks, panel (g)) and CSF1R (green sticks, panel (h)). Compound 19, KITC809 and CSF1RG795 are depicted as transparent surfaces. The gatekeeper residues (KITT670 and CSF1RT663) as well as other protein residues are depicted as sticks in order to allow a better comprehension of the compound binding modes.

Mentions: To rationalize the selectivity profile showed by compounds 19 and 27, we firstly analyzed some key residues of the ATP-pocket usually involved in the binding of TKIs (Fig. 8a).


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)

Binding mode study on compounds 19 and 27.(a) Sequences of hinge, DGF and hydrophobic pocket I regions of the ATP binding pocket for class III RTKs. Black (or red) characters indicate amino acids that place the side chain inside the ATP-pocket; grey characters indicate the amino acids that place the side chain outside the ATP-pocket. Amino acids that place the side chain inside the ATP-pocket and that differ between the five kinases are highlighted in red. The gatekeeper residue number is also reported. (b–f) Results of docking simulations: (b) Potential binding mode of 19 (gray stick) with KIT (green sticks); (c) Potential binding mode of 27 (blue stick) with KIT (green sticks); (d) Potential binding mode of 19 (yellow sticks) with CSF1R (pink sticks); (e) Potential binding mode of 19 (light pink sticks) with FLT3 (cyan sticks); (f) Potential binding mode of 27 (blue sticks) with KIT (green sticks and green cartoons), in context with the ATP binding site features. The 6-phenyl moiety of compound 27 is placed in the hydrophobic pocket II, whereas the hydrophilic function (i.e. the morpholine ring) is placed in the ribose pocket. (g,h) Details of docking simulations for compound 19 (yellow sticks) in KIT (blue sticks, panel (g)) and CSF1R (green sticks, panel (h)). Compound 19, KITC809 and CSF1RG795 are depicted as transparent surfaces. The gatekeeper residues (KITT670 and CSF1RT663) as well as other protein residues are depicted as sticks in order to allow a better comprehension of the compound binding modes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Binding mode study on compounds 19 and 27.(a) Sequences of hinge, DGF and hydrophobic pocket I regions of the ATP binding pocket for class III RTKs. Black (or red) characters indicate amino acids that place the side chain inside the ATP-pocket; grey characters indicate the amino acids that place the side chain outside the ATP-pocket. Amino acids that place the side chain inside the ATP-pocket and that differ between the five kinases are highlighted in red. The gatekeeper residue number is also reported. (b–f) Results of docking simulations: (b) Potential binding mode of 19 (gray stick) with KIT (green sticks); (c) Potential binding mode of 27 (blue stick) with KIT (green sticks); (d) Potential binding mode of 19 (yellow sticks) with CSF1R (pink sticks); (e) Potential binding mode of 19 (light pink sticks) with FLT3 (cyan sticks); (f) Potential binding mode of 27 (blue sticks) with KIT (green sticks and green cartoons), in context with the ATP binding site features. The 6-phenyl moiety of compound 27 is placed in the hydrophobic pocket II, whereas the hydrophilic function (i.e. the morpholine ring) is placed in the ribose pocket. (g,h) Details of docking simulations for compound 19 (yellow sticks) in KIT (blue sticks, panel (g)) and CSF1R (green sticks, panel (h)). Compound 19, KITC809 and CSF1RG795 are depicted as transparent surfaces. The gatekeeper residues (KITT670 and CSF1RT663) as well as other protein residues are depicted as sticks in order to allow a better comprehension of the compound binding modes.
Mentions: To rationalize the selectivity profile showed by compounds 19 and 27, we firstly analyzed some key residues of the ATP-pocket usually involved in the binding of TKIs (Fig. 8a).

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