Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to...
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th-mahidol.313102018-10-19T12:44:10Z Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach Kingkan Sanphanya Suvara K. Wattanapitayakul Suwadee Phowichit Valery V. Fokin Opa Vajragupta Mahidol University Srinakharinwirot University Scripps Research Institute Biochemistry, Genetics and Molecular Biology Chemistry Pharmacology, Toxicology and Pharmaceutics We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1, 2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50against VEGFR-2 of 0.56 μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization. © 2013 Elsevier Ltd. All rights reserved. 2018-10-19T04:39:29Z 2018-10-19T04:39:29Z 2013-05-15 Article Bioorganic and Medicinal Chemistry Letters. Vol.23, No.10 (2013), 2962-2967 10.1016/j.bmcl.2013.03.042 14643405 0960894X 2-s2.0-84876669366 https://repository.li.mahidol.ac.th/handle/123456789/31310 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84876669366&origin=inward |
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Biochemistry, Genetics and Molecular Biology Chemistry Pharmacology, Toxicology and Pharmaceutics Kingkan Sanphanya Suvara K. Wattanapitayakul Suwadee Phowichit Valery V. Fokin Opa Vajragupta Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
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We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1, 2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50against VEGFR-2 of 0.56 μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization. © 2013 Elsevier Ltd. All rights reserved. |
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Mahidol University |
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Mahidol University Kingkan Sanphanya Suvara K. Wattanapitayakul Suwadee Phowichit Valery V. Fokin Opa Vajragupta |
| format |
Article |
| author |
Kingkan Sanphanya Suvara K. Wattanapitayakul Suwadee Phowichit Valery V. Fokin Opa Vajragupta |
| author_sort |
Kingkan Sanphanya |
| title |
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
| title_short |
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
| title_full |
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
| title_fullStr |
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
| title_full_unstemmed |
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach |
| title_sort |
novel vegfr-2 kinase inhibitors identified by the back-to-front approach |
| publishDate |
2018 |
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https://repository.li.mahidol.ac.th/handle/123456789/31310 |
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1763488042464575488 |