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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

Predicted docking orientation of MKP101 in the epidermal growth factor receptor (EGFR) kinase domain.The binding poses of (A) MKP101 (carbon atoms in green) and (B) pazopanib (carbon atoms in orange) in the human EGFR kinase domain were compared. The structure of co-crystallized TAK-285 is shown as a reference (carbon atoms in off-white). 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. A 2D-interaction diagram of the binding model of (C) MKP101 and (D) pazopanib was generated, which displayed amino acid residues within 4.0 Å 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. Hydrogen bonds between the ligand and the backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. The docking models show that MKP101 occupies the ATP-binding site in a manner similar to TAK-285, and the indole ring of MKP101 interacts with the backbone of the Phe856 by hydrogen bonding. However, as expected, pazopanib did not fit well at the ATP binding site. 2D, 2-dimensional; ATP, adenosine triphosphate.
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pone.0138823.g005: Predicted docking orientation of MKP101 in the epidermal growth factor receptor (EGFR) kinase domain.The binding poses of (A) MKP101 (carbon atoms in green) and (B) pazopanib (carbon atoms in orange) in the human EGFR kinase domain were compared. The structure of co-crystallized TAK-285 is shown as a reference (carbon atoms in off-white). 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. A 2D-interaction diagram of the binding model of (C) MKP101 and (D) pazopanib was generated, which displayed amino acid residues within 4.0 Å 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. Hydrogen bonds between the ligand and the backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. The docking models show that MKP101 occupies the ATP-binding site in a manner similar to TAK-285, and the indole ring of MKP101 interacts with the backbone of the Phe856 by hydrogen bonding. However, as expected, pazopanib did not fit well at the ATP binding site. 2D, 2-dimensional; ATP, adenosine triphosphate.

Mentions: The top-scored binding configurations and a schematic 2-dimensional (2D) representation of MKP101 and pazopanib co-crystallized with TAK-285 as a reference are shown in Fig 4. MKP101 occupies the ATP binding site of the EGFR in a manner similar to TAK-285. The indole ring of MKP101 occupies a lipophilic pocket formed by Met766, Cys775, Leu777, Leu788, and Phe856 in a manner similar to that observed with the 3-trifluoromethylphenyl group of TAK-285, and forms a direct hydrogen bond to the backbone of Phe856 (Fig 5A and 5C). The aniline moiety of MKP101 was docked in the hinge region between the N- and C-lobes, similar to the pyrrolo[3,2-d]pyrimidine ring of TAK-285, where it participates in hydrophobic interactions with Leu718, Leu844, Leu792, and Met793 (Fig 5A and 5C). The sulfonamide group of MKP101 was exposed to the solvent in a manner similar to that observed for hydroxymethylbutanamide moiety of TAK-285. Pazopanib did not fit as well as MKP101 and TAK-285 at the ATP binding site (Fig 5B and 5D). The rigid and bulky dimethylindazole group of pazopanib does not participate in hydrogen bond interaction with Phe856, and cannot fit into the lipophilic pocket of the EGFR. Consequently, the aniline moiety of pazopanib, which did not occupy the hinge region, was exposed to the solvent (Fig 5B and 5D).


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)

Predicted docking orientation of MKP101 in the epidermal growth factor receptor (EGFR) kinase domain.The binding poses of (A) MKP101 (carbon atoms in green) and (B) pazopanib (carbon atoms in orange) in the human EGFR kinase domain were compared. The structure of co-crystallized TAK-285 is shown as a reference (carbon atoms in off-white). 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. A 2D-interaction diagram of the binding model of (C) MKP101 and (D) pazopanib was generated, which displayed amino acid residues within 4.0 Å 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. Hydrogen bonds between the ligand and the backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. The docking models show that MKP101 occupies the ATP-binding site in a manner similar to TAK-285, and the indole ring of MKP101 interacts with the backbone of the Phe856 by hydrogen bonding. However, as expected, pazopanib did not fit well at the ATP binding site. 2D, 2-dimensional; ATP, adenosine triphosphate.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0138823.g005: Predicted docking orientation of MKP101 in the epidermal growth factor receptor (EGFR) kinase domain.The binding poses of (A) MKP101 (carbon atoms in green) and (B) pazopanib (carbon atoms in orange) in the human EGFR kinase domain were compared. The structure of co-crystallized TAK-285 is shown as a reference (carbon atoms in off-white). 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. A 2D-interaction diagram of the binding model of (C) MKP101 and (D) pazopanib was generated, which displayed amino acid residues within 4.0 Å 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. Hydrogen bonds between the ligand and the backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. The docking models show that MKP101 occupies the ATP-binding site in a manner similar to TAK-285, and the indole ring of MKP101 interacts with the backbone of the Phe856 by hydrogen bonding. However, as expected, pazopanib did not fit well at the ATP binding site. 2D, 2-dimensional; ATP, adenosine triphosphate.
Mentions: The top-scored binding configurations and a schematic 2-dimensional (2D) representation of MKP101 and pazopanib co-crystallized with TAK-285 as a reference are shown in Fig 4. MKP101 occupies the ATP binding site of the EGFR in a manner similar to TAK-285. The indole ring of MKP101 occupies a lipophilic pocket formed by Met766, Cys775, Leu777, Leu788, and Phe856 in a manner similar to that observed with the 3-trifluoromethylphenyl group of TAK-285, and forms a direct hydrogen bond to the backbone of Phe856 (Fig 5A and 5C). The aniline moiety of MKP101 was docked in the hinge region between the N- and C-lobes, similar to the pyrrolo[3,2-d]pyrimidine ring of TAK-285, where it participates in hydrophobic interactions with Leu718, Leu844, Leu792, and Met793 (Fig 5A and 5C). The sulfonamide group of MKP101 was exposed to the solvent in a manner similar to that observed for hydroxymethylbutanamide moiety of TAK-285. Pazopanib did not fit as well as MKP101 and TAK-285 at the ATP binding site (Fig 5B and 5D). The rigid and bulky dimethylindazole group of pazopanib does not participate in hydrogen bond interaction with Phe856, and cannot fit into the lipophilic pocket of the EGFR. Consequently, the aniline moiety of pazopanib, which did not occupy the hinge region, was exposed to the solvent (Fig 5B and 5D).

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