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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

Structures of MKP102, MKP103, MKP104, and MKP105.MKP102 and 103 are derivatives that possess a methyl group at the C-3 and C-2 positions of the indole ring, respectively. MKP104 is a derivative with a methyl group on the indole nitrogen. MKP105 is a regioisomer of MKP101.
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pone.0138823.g006: Structures of MKP102, MKP103, MKP104, and MKP105.MKP102 and 103 are derivatives that possess a methyl group at the C-3 and C-2 positions of the indole ring, respectively. MKP104 is a derivative with a methyl group on the indole nitrogen. MKP105 is a regioisomer of MKP101.

Mentions: The indole derivatives of MKP101 (MKP102-105) were synthesized to determine the effect of the indole moiety on EGFR activity and to validate the molecular docking model of MKP101 and EGFR. This model of EGFR-MKP101 showed that there appeared to be a space available at the C3 position of the indole moiety, but the space at the C-2 position appeared to be very limited. Therefore, we introduced a methyl group at the C-2 or C-3 position of the indole moiety, and MKP102 (a 3-methyl indole) and MKP103 (a 2-methyl indole) were synthesized (Fig 6). To determine whether the hydrogen bonding interaction of the amine of the indole moiety is essential, the N-methylated derivative MKP104 and its regioisomer MKP105 were synthesized. The MKP compounds (MKP102–105) were subjected to an in vitro kinase assay for determination of EGFR inhibitory activity (Table 3). As expected based on the docking model, only MKP102 showed significant activity in the in vitro kinase assay while the other MKP compounds showed very poor activity against EGFR. In addition, the MKP compounds were evaluated for anti-proliferative activity in HCC827 cells (Table 3). Only MKP102 displayed significant anti-proliferative activity (IC50, 197 nM) against HCC827 cells in a manner similar to that observed with MKP101. The anti-proliferative activity correlated well with the results of the kinase assay for EGFR.


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)

Structures of MKP102, MKP103, MKP104, and MKP105.MKP102 and 103 are derivatives that possess a methyl group at the C-3 and C-2 positions of the indole ring, respectively. MKP104 is a derivative with a methyl group on the indole nitrogen. MKP105 is a regioisomer of MKP101.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0138823.g006: Structures of MKP102, MKP103, MKP104, and MKP105.MKP102 and 103 are derivatives that possess a methyl group at the C-3 and C-2 positions of the indole ring, respectively. MKP104 is a derivative with a methyl group on the indole nitrogen. MKP105 is a regioisomer of MKP101.
Mentions: The indole derivatives of MKP101 (MKP102-105) were synthesized to determine the effect of the indole moiety on EGFR activity and to validate the molecular docking model of MKP101 and EGFR. This model of EGFR-MKP101 showed that there appeared to be a space available at the C3 position of the indole moiety, but the space at the C-2 position appeared to be very limited. Therefore, we introduced a methyl group at the C-2 or C-3 position of the indole moiety, and MKP102 (a 3-methyl indole) and MKP103 (a 2-methyl indole) were synthesized (Fig 6). To determine whether the hydrogen bonding interaction of the amine of the indole moiety is essential, the N-methylated derivative MKP104 and its regioisomer MKP105 were synthesized. The MKP compounds (MKP102–105) were subjected to an in vitro kinase assay for determination of EGFR inhibitory activity (Table 3). As expected based on the docking model, only MKP102 showed significant activity in the in vitro kinase assay while the other MKP compounds showed very poor activity against EGFR. In addition, the MKP compounds were evaluated for anti-proliferative activity in HCC827 cells (Table 3). Only MKP102 displayed significant anti-proliferative activity (IC50, 197 nM) against HCC827 cells in a manner similar to that observed with MKP101. The anti-proliferative activity correlated well with the results of the kinase assay for EGFR.

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