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Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.

Song J, Yoo J, Kwon A, Kim D, Nguyen HK, Lee BY, Suh W, Min KH - PLoS ONE (2015)

Bottom Line: MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib.A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives.We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

ABSTRACT
Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

No MeSH data available.


Related in: MedlinePlus

Comparison of the binding poses of MKP123 and MKP122 with MKP101.Binding poses of (A) MKP123 (carbon atoms in green) and (B) MKP122 (carbon atoms in green) with MKP101 (carbon atoms in ivory). The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. 2D-interaction diagram of the binding model of (C) MKP123 and (D) MKP122 displaying the amino acid residues within 4.0Å of the ligand. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. The hydrogen bond between the ligand and backbone is shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Unlike MKP101, the indole rings of MKP123 and MKP122 occupy a lipophilic pocket without a hydrogen bond with the backbone of Phe856, and their aniline moiety was docked in the hinge region. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor.
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pone.0138823.g009: Comparison of the binding poses of MKP123 and MKP122 with MKP101.Binding poses of (A) MKP123 (carbon atoms in green) and (B) MKP122 (carbon atoms in green) with MKP101 (carbon atoms in ivory). The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. 2D-interaction diagram of the binding model of (C) MKP123 and (D) MKP122 displaying the amino acid residues within 4.0Å of the ligand. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. The hydrogen bond between the ligand and backbone is shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Unlike MKP101, the indole rings of MKP123 and MKP122 occupy a lipophilic pocket without a hydrogen bond with the backbone of Phe856, and their aniline moiety was docked in the hinge region. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor.

Mentions: The binding models of MKP122 and MKP123 were generated and compared with the reference model, MKP101 (Fig 9). MKP122 and MKP123, which had flexible ether linkages, showed a binding position similar to MKP101. The indole rings of MKP123 and MKP122 were deeply placed into lipophilic pockets without a hydrogen bond with the backbone of Phe856 and their aniline moieties were docked in the hinge region. However, the calculated docking scores of MKP123 were lower than those of MKP122 (-9.6 and -8.1 kcal/mol, respectively) and therefore, more favorable. Apparently, this is owing to the difference in the electrostatic and van der Waals energies created by 6-indolyloxy-pyrimidine of MKP123 and 4-indolyloxy pyrimidine of MKP122. MKP123 showed a more favorable docking score (-9.6 kcal/mol) compared to the score that was calculated for MKP101 (-8.9 kcal/mol). The rank order of the docking scores of MKP123, MKP101, and MKP122 was consistent with the results of the experimental EGFR inhibition assays.


Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.

Song J, Yoo J, Kwon A, Kim D, Nguyen HK, Lee BY, Suh W, Min KH - PLoS ONE (2015)

Comparison of the binding poses of MKP123 and MKP122 with MKP101.Binding poses of (A) MKP123 (carbon atoms in green) and (B) MKP122 (carbon atoms in green) with MKP101 (carbon atoms in ivory). The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. 2D-interaction diagram of the binding model of (C) MKP123 and (D) MKP122 displaying the amino acid residues within 4.0Å of the ligand. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. The hydrogen bond between the ligand and backbone is shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Unlike MKP101, the indole rings of MKP123 and MKP122 occupy a lipophilic pocket without a hydrogen bond with the backbone of Phe856, and their aniline moiety was docked in the hinge region. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581874&req=5

pone.0138823.g009: Comparison of the binding poses of MKP123 and MKP122 with MKP101.Binding poses of (A) MKP123 (carbon atoms in green) and (B) MKP122 (carbon atoms in green) with MKP101 (carbon atoms in ivory). The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. 2D-interaction diagram of the binding model of (C) MKP123 and (D) MKP122 displaying the amino acid residues within 4.0Å of the ligand. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. The hydrogen bond between the ligand and backbone is shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Unlike MKP101, the indole rings of MKP123 and MKP122 occupy a lipophilic pocket without a hydrogen bond with the backbone of Phe856, and their aniline moiety was docked in the hinge region. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor.
Mentions: The binding models of MKP122 and MKP123 were generated and compared with the reference model, MKP101 (Fig 9). MKP122 and MKP123, which had flexible ether linkages, showed a binding position similar to MKP101. The indole rings of MKP123 and MKP122 were deeply placed into lipophilic pockets without a hydrogen bond with the backbone of Phe856 and their aniline moieties were docked in the hinge region. However, the calculated docking scores of MKP123 were lower than those of MKP122 (-9.6 and -8.1 kcal/mol, respectively) and therefore, more favorable. Apparently, this is owing to the difference in the electrostatic and van der Waals energies created by 6-indolyloxy-pyrimidine of MKP123 and 4-indolyloxy pyrimidine of MKP122. MKP123 showed a more favorable docking score (-9.6 kcal/mol) compared to the score that was calculated for MKP101 (-8.9 kcal/mol). The rank order of the docking scores of MKP123, MKP101, and MKP122 was consistent with the results of the experimental EGFR inhibition assays.

Bottom Line: MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib.A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives.We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

ABSTRACT
Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

No MeSH data available.


Related in: MedlinePlus