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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 the indole tethered pyrimidine derivatives.
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pone.0138823.g008: Structures of the indole tethered pyrimidine derivatives.

Mentions: Next, different indole analogs for aniline moiety on the other side were synthesized to determine their effects on affinity for EGFR, based on the above results (Fig 8). The The SAR study was conducted using easily synthesized morpholine derivatives. As shown in Table 4, the synthesized compounds were evaluated for activity against EGFR and VEGFR-2. Firstly, the morpholinoethoxyaniline compound, MKP106 showed activity against VEGFR-2 with comparable potency to MKP101, as well as activity against EGFR that was weaker than that of MKP101. Two-carbon extended compound MKP107 retained activity for EGFR but its effect for VEGFR-2 slightly decreased, compared to MKP106. N-methylation of MKP107 (MKP108) greatly improved its activity against VEGFR-2 and maintained its activity against EGFR, indicating that N-methylation has a positive effect on the binding with VEGFR-2 without affecting EGFR. In morpholinoaniline derivatives, meta substitution of morpholine (MKP110) led to slightly improved activity over para substitution (MKP109) against both EGFR and VEGFR. However, the introduction of fluoride, a strong electron-withdrawing group (MKP114 and 113) significantly decreased the activity against EGFR and retained the activity against VEGFR-2. In contrast, the introduction of an electron-donating methoxy group (MKP116 and 115) increased the activity against EGFR and VEGFR-2. Unlike MKP108, N-methylation of MKP116 (MKP117) maintained the activity against EGFR and VEGFR-2 without significant change for VEGFR-2. N-methyl indole derivatives MKP112 and MKP111 showed poor EGFR activity, as expected from the docking study, clearly demonstrating that the NH group of indole is essential for binding to EGFR. Next, we investigated the SAR associated with changes in substitution from 2,4-disubsitututed to 4,6-disubstituted pyrimidine. MKP118, 4,6-dianilino derivative showed excellent activity against EGFR; however, this activity was not as significant as that of MKP109. The N-methylated compound MKP119 also showed poor activity against VEGFR-2, but had a high affinity for EGFR. An O-bridge was introduced between indole and pyrimidine, replacing the N-bridge provided by aniline. Interestingly, the arylether MKP120 showed excellent concurrent inhibition of EGFR and VEGFR-2 with IC50 values of 10 and 32 nM, respectively. MKP121 also exhibited high activity against EGFR and VEGFR-2. These studies were also conducted with arylether derivatives of MKP101. The 2,4-disubstituted pyrimidine MKP122 showed potent activity against VEGFR-2 but poor activity against EGFR. However, the 4,6-disubstituted pyrimidine MKP123 showed potent concurrent inhibition of EGFR and VEGFR-2, with IC50 values of 18 and 45 nM, respectively. Taken together, these results suggest that the 4-indolyloxy-6-anilinopyrimidines could be a key structural requirement for significant inhibitory activity against EGFR and VEGFR-2. Selected compounds were screened against some angiokinases to determine the effects of structural modification on anti-angiokinase activity. The kinase profiles of these compounds are presented in Table 5. As mentioned previously, MKP101 effectively inhibited key angiokinases. The replacement of methylated nitrogen with oxygen, as in MKP122, reduced activity against EGFR and FGFR. The 4-indolyloxy pyrimidines including MKP121 and MKP123, which is a regioisomer of MKP122, retained high potency for EGFRs and VEGFRs. However, their activity against cKIT slightly decreased while that against FGFR and PDGFR markedly decreased. Differences in selectivity for angiokinases were observed between the N- and O-bridge, and the 2,4- and 4,6-disubstituted pyrimidines. To elucidate the difference, we carried out further molecular docking studies based on the docking model of EGFR-MKP101.


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 the indole tethered pyrimidine derivatives.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0138823.g008: Structures of the indole tethered pyrimidine derivatives.
Mentions: Next, different indole analogs for aniline moiety on the other side were synthesized to determine their effects on affinity for EGFR, based on the above results (Fig 8). The The SAR study was conducted using easily synthesized morpholine derivatives. As shown in Table 4, the synthesized compounds were evaluated for activity against EGFR and VEGFR-2. Firstly, the morpholinoethoxyaniline compound, MKP106 showed activity against VEGFR-2 with comparable potency to MKP101, as well as activity against EGFR that was weaker than that of MKP101. Two-carbon extended compound MKP107 retained activity for EGFR but its effect for VEGFR-2 slightly decreased, compared to MKP106. N-methylation of MKP107 (MKP108) greatly improved its activity against VEGFR-2 and maintained its activity against EGFR, indicating that N-methylation has a positive effect on the binding with VEGFR-2 without affecting EGFR. In morpholinoaniline derivatives, meta substitution of morpholine (MKP110) led to slightly improved activity over para substitution (MKP109) against both EGFR and VEGFR. However, the introduction of fluoride, a strong electron-withdrawing group (MKP114 and 113) significantly decreased the activity against EGFR and retained the activity against VEGFR-2. In contrast, the introduction of an electron-donating methoxy group (MKP116 and 115) increased the activity against EGFR and VEGFR-2. Unlike MKP108, N-methylation of MKP116 (MKP117) maintained the activity against EGFR and VEGFR-2 without significant change for VEGFR-2. N-methyl indole derivatives MKP112 and MKP111 showed poor EGFR activity, as expected from the docking study, clearly demonstrating that the NH group of indole is essential for binding to EGFR. Next, we investigated the SAR associated with changes in substitution from 2,4-disubsitututed to 4,6-disubstituted pyrimidine. MKP118, 4,6-dianilino derivative showed excellent activity against EGFR; however, this activity was not as significant as that of MKP109. The N-methylated compound MKP119 also showed poor activity against VEGFR-2, but had a high affinity for EGFR. An O-bridge was introduced between indole and pyrimidine, replacing the N-bridge provided by aniline. Interestingly, the arylether MKP120 showed excellent concurrent inhibition of EGFR and VEGFR-2 with IC50 values of 10 and 32 nM, respectively. MKP121 also exhibited high activity against EGFR and VEGFR-2. These studies were also conducted with arylether derivatives of MKP101. The 2,4-disubstituted pyrimidine MKP122 showed potent activity against VEGFR-2 but poor activity against EGFR. However, the 4,6-disubstituted pyrimidine MKP123 showed potent concurrent inhibition of EGFR and VEGFR-2, with IC50 values of 18 and 45 nM, respectively. Taken together, these results suggest that the 4-indolyloxy-6-anilinopyrimidines could be a key structural requirement for significant inhibitory activity against EGFR and VEGFR-2. Selected compounds were screened against some angiokinases to determine the effects of structural modification on anti-angiokinase activity. The kinase profiles of these compounds are presented in Table 5. As mentioned previously, MKP101 effectively inhibited key angiokinases. The replacement of methylated nitrogen with oxygen, as in MKP122, reduced activity against EGFR and FGFR. The 4-indolyloxy pyrimidines including MKP121 and MKP123, which is a regioisomer of MKP122, retained high potency for EGFRs and VEGFRs. However, their activity against cKIT slightly decreased while that against FGFR and PDGFR markedly decreased. Differences in selectivity for angiokinases were observed between the N- and O-bridge, and the 2,4- and 4,6-disubstituted pyrimidines. To elucidate the difference, we carried out further molecular docking studies based on the docking model of EGFR-MKP101.

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