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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 configurations of the MKP101 analogues.(A) MKP102, (B) MKP103, (C) MKP104, and (D) MKP105 (carbon atoms in green) with TAK-285 (carbon atoms in ivory). Hydrogen bonds are displayed as dashed lines. The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. In the 2D-interaction diagram, acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Similar to MKP101, the 3-methyl indole moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond with the backbone of Phe856. However, MKP103 the 2-methyl indole derivative, cannot fit into the lipophilic pocket because of the steric hindrance of the methyl group. The N-methyl indole MKP104 and the 6-amino indole MKP105 lost hydrogen bonding with Phe856 owing to the structural change. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; 2D, 2-dimensional.
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pone.0138823.g007: Comparison of the binding configurations of the MKP101 analogues.(A) MKP102, (B) MKP103, (C) MKP104, and (D) MKP105 (carbon atoms in green) with TAK-285 (carbon atoms in ivory). Hydrogen bonds are displayed as dashed lines. The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. In the 2D-interaction diagram, acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Similar to MKP101, the 3-methyl indole moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond with the backbone of Phe856. However, MKP103 the 2-methyl indole derivative, cannot fit into the lipophilic pocket because of the steric hindrance of the methyl group. The N-methyl indole MKP104 and the 6-amino indole MKP105 lost hydrogen bonding with Phe856 owing to the structural change. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; 2D, 2-dimensional.

Mentions: Further docking studies of the MKP101 derivatives were carried out to explore their SAR. Fig 7 shows a comparison of the predicted binding mode of the analogs of MKP101. MKP102 showed anti-proliferative activity comparable to that of MKP101, and a similar binding configuration. The 3-methyl indole amino moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond to the backbone of the Phe856 in the same orientation as the indole ring of MKP101 (Fig 7). In contrast, MKP103, with its 2-methyl indole group, could not fit into the lipophilic pocket (similar to pazopanib), and showed anti-proliferative activity that was dramatically weaker than that shown by MKP101 (Fig 7). The 5-amino-N-methyl indole of MKP104 also lacked a hydrogen bonding interaction with the Phe856 at the lipophilic pocket and showed a corresponding substantial decrease in inhibitory activity (Fig 7). The binding configuration of the 6-amino indole of MKP105 was flipped compared to the 5-amino indole analogues. As a result, MKP105 also lost the hydrogen bond interaction with the Phe856 at the lipophilic pocket, which decreased its inhibitory activity (Fig 7). The docking results showed that a lipophilic pocket with limited space and a hinge region surrounded MKP101 at the ATP binding site and hydrogen bonding with Phe856 at the lipophilic pocket is particularly important for potency. Taken together, the findings of the docking studies are in agreement with the enzymatic inhibitory activity assays and provide essential information for the design of a potent EGFR inhibitor.


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 configurations of the MKP101 analogues.(A) MKP102, (B) MKP103, (C) MKP104, and (D) MKP105 (carbon atoms in green) with TAK-285 (carbon atoms in ivory). Hydrogen bonds are displayed as dashed lines. The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. In the 2D-interaction diagram, acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Similar to MKP101, the 3-methyl indole moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond with the backbone of Phe856. However, MKP103 the 2-methyl indole derivative, cannot fit into the lipophilic pocket because of the steric hindrance of the methyl group. The N-methyl indole MKP104 and the 6-amino indole MKP105 lost hydrogen bonding with Phe856 owing to the structural change. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; 2D, 2-dimensional.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0138823.g007: Comparison of the binding configurations of the MKP101 analogues.(A) MKP102, (B) MKP103, (C) MKP104, and (D) MKP105 (carbon atoms in green) with TAK-285 (carbon atoms in ivory). Hydrogen bonds are displayed as dashed lines. The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. In the 2D-interaction diagram, acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Similar to MKP101, the 3-methyl indole moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond with the backbone of Phe856. However, MKP103 the 2-methyl indole derivative, cannot fit into the lipophilic pocket because of the steric hindrance of the methyl group. The N-methyl indole MKP104 and the 6-amino indole MKP105 lost hydrogen bonding with Phe856 owing to the structural change. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; 2D, 2-dimensional.
Mentions: Further docking studies of the MKP101 derivatives were carried out to explore their SAR. Fig 7 shows a comparison of the predicted binding mode of the analogs of MKP101. MKP102 showed anti-proliferative activity comparable to that of MKP101, and a similar binding configuration. The 3-methyl indole amino moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond to the backbone of the Phe856 in the same orientation as the indole ring of MKP101 (Fig 7). In contrast, MKP103, with its 2-methyl indole group, could not fit into the lipophilic pocket (similar to pazopanib), and showed anti-proliferative activity that was dramatically weaker than that shown by MKP101 (Fig 7). The 5-amino-N-methyl indole of MKP104 also lacked a hydrogen bonding interaction with the Phe856 at the lipophilic pocket and showed a corresponding substantial decrease in inhibitory activity (Fig 7). The binding configuration of the 6-amino indole of MKP105 was flipped compared to the 5-amino indole analogues. As a result, MKP105 also lost the hydrogen bond interaction with the Phe856 at the lipophilic pocket, which decreased its inhibitory activity (Fig 7). The docking results showed that a lipophilic pocket with limited space and a hinge region surrounded MKP101 at the ATP binding site and hydrogen bonding with Phe856 at the lipophilic pocket is particularly important for potency. Taken together, the findings of the docking studies are in agreement with the enzymatic inhibitory activity assays and provide essential information for the design of a potent EGFR inhibitor.

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