Publication: Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
Issued Date
2013-05-15
Resource Type
ISSN
14643405
0960894X
0960894X
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2-s2.0-84876669366
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Mahidol University
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SCOPUS
Bibliographic Citation
Bioorganic and Medicinal Chemistry Letters. Vol.23, No.10 (2013), 2962-2967
Suggested Citation
Kingkan Sanphanya, Suvara K. Wattanapitayakul, Suwadee Phowichit, Valery V. Fokin, Opa Vajragupta Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach. Bioorganic and Medicinal Chemistry Letters. Vol.23, No.10 (2013), 2962-2967. doi:10.1016/j.bmcl.2013.03.042 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/31310
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Title
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
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Abstract
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.