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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

Pazopanib and MKP101 have similar inhibitory effects on VEGF-induced angiogenesis in HUVECs.(A) Cytotoxicity of pazopanib and MKP101 in HUVECs. No cytotoxicity was observed at 1 μg/mL pazopanib or 1 μg/mL MKP101. (B-D) Pazopanib and MKP101 block VEGF (50 ng/ml)-induced increases in endothelial proliferation (B), tube formation (C), and migration (D). Cell proliferation and tube formation experiments were performed using 1 μg/mL of pazopanib and 1 μg/mL MKP101. The scratch wound migration assay was performed using 0.5 μg/mL pazopanib and 0.5 μg/mL MKP101. In (A) and (B), the number of cells was expressed as the fold change with respect to the number of cells seeded at day 0. Tube formation responses were compared by normalizing the values relative to those of the corresponding PBS control samples (*p < 0.05 vs. PBS; #p < 0.05 vs. VEGF, mean ± SEM). Scale bar = 100 μm.
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pone.0138823.g004: Pazopanib and MKP101 have similar inhibitory effects on VEGF-induced angiogenesis in HUVECs.(A) Cytotoxicity of pazopanib and MKP101 in HUVECs. No cytotoxicity was observed at 1 μg/mL pazopanib or 1 μg/mL MKP101. (B-D) Pazopanib and MKP101 block VEGF (50 ng/ml)-induced increases in endothelial proliferation (B), tube formation (C), and migration (D). Cell proliferation and tube formation experiments were performed using 1 μg/mL of pazopanib and 1 μg/mL MKP101. The scratch wound migration assay was performed using 0.5 μg/mL pazopanib and 0.5 μg/mL MKP101. In (A) and (B), the number of cells was expressed as the fold change with respect to the number of cells seeded at day 0. Tube formation responses were compared by normalizing the values relative to those of the corresponding PBS control samples (*p < 0.05 vs. PBS; #p < 0.05 vs. VEGF, mean ± SEM). Scale bar = 100 μm.

Mentions: Non-cytotoxic concentrations of pazopanib and MKP101 were tested in human umbilical vein endothelial cells (HUVECs) prior to the angiogenesis assays. Pazopanib and MKP101 exhibited significant endothelial cytotoxicity at 5 and 10 μg/mL, but not at 1 μg/mL (Fig 4A). Therefore, in vitro angiogenesis assays were performed with pazopanib and MKP101 at non-cytotoxic concentrations 1 μg/mL for both, and their inhibitory effects against VEGF-triggered angiogenesis were evaluated. As shown in Fig 4B–4D, in vitro angiogenesis data revealed that VEGF-induced increases in endothelial proliferation, tube formation, and migration were significantly inhibited by pazopanib and MKP101. MKP101 blocked the VEGF-mediated angiogenic activity of endothelial cells with potency comparable to that of pazopanib.


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)

Pazopanib and MKP101 have similar inhibitory effects on VEGF-induced angiogenesis in HUVECs.(A) Cytotoxicity of pazopanib and MKP101 in HUVECs. No cytotoxicity was observed at 1 μg/mL pazopanib or 1 μg/mL MKP101. (B-D) Pazopanib and MKP101 block VEGF (50 ng/ml)-induced increases in endothelial proliferation (B), tube formation (C), and migration (D). Cell proliferation and tube formation experiments were performed using 1 μg/mL of pazopanib and 1 μg/mL MKP101. The scratch wound migration assay was performed using 0.5 μg/mL pazopanib and 0.5 μg/mL MKP101. In (A) and (B), the number of cells was expressed as the fold change with respect to the number of cells seeded at day 0. Tube formation responses were compared by normalizing the values relative to those of the corresponding PBS control samples (*p < 0.05 vs. PBS; #p < 0.05 vs. VEGF, mean ± SEM). Scale bar = 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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pone.0138823.g004: Pazopanib and MKP101 have similar inhibitory effects on VEGF-induced angiogenesis in HUVECs.(A) Cytotoxicity of pazopanib and MKP101 in HUVECs. No cytotoxicity was observed at 1 μg/mL pazopanib or 1 μg/mL MKP101. (B-D) Pazopanib and MKP101 block VEGF (50 ng/ml)-induced increases in endothelial proliferation (B), tube formation (C), and migration (D). Cell proliferation and tube formation experiments were performed using 1 μg/mL of pazopanib and 1 μg/mL MKP101. The scratch wound migration assay was performed using 0.5 μg/mL pazopanib and 0.5 μg/mL MKP101. In (A) and (B), the number of cells was expressed as the fold change with respect to the number of cells seeded at day 0. Tube formation responses were compared by normalizing the values relative to those of the corresponding PBS control samples (*p < 0.05 vs. PBS; #p < 0.05 vs. VEGF, mean ± SEM). Scale bar = 100 μm.
Mentions: Non-cytotoxic concentrations of pazopanib and MKP101 were tested in human umbilical vein endothelial cells (HUVECs) prior to the angiogenesis assays. Pazopanib and MKP101 exhibited significant endothelial cytotoxicity at 5 and 10 μg/mL, but not at 1 μg/mL (Fig 4A). Therefore, in vitro angiogenesis assays were performed with pazopanib and MKP101 at non-cytotoxic concentrations 1 μg/mL for both, and their inhibitory effects against VEGF-triggered angiogenesis were evaluated. As shown in Fig 4B–4D, in vitro angiogenesis data revealed that VEGF-induced increases in endothelial proliferation, tube formation, and migration were significantly inhibited by pazopanib and MKP101. MKP101 blocked the VEGF-mediated angiogenic activity of endothelial cells with potency comparable to that of pazopanib.

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