Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach

Kingkan Sanphanya, Suvara K. Wattanapitayakul, Suwadee Phowichit, Valery V. Fokin, Opa Vajragupta

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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 IC₅₀ against 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.

Original language	English
Pages (from-to)	2962-2967
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.042
Publication status	Published - 15 May 2013
Externally published	Yes

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Keywords

VEGFR-2 KDR VEGFR-2 inhibitor Molecular modeling Antiangiogenesis 1,4-Disubstituted 1,2,3-triazoles CuAAC reaction

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

Cite this

Sanphanya, K., Wattanapitayakul, S. K., Phowichit, S., Fokin, V. V., & Vajragupta, O. (2013). Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach. Bioorganic and Medicinal Chemistry Letters, 23(10), 2962-2967. https://doi.org/10.1016/j.bmcl.2013.03.042

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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 IC50 against 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.",

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author = "Kingkan Sanphanya and Wattanapitayakul, {Suvara K.} and Suwadee Phowichit and Fokin, {Valery V.} and Opa Vajragupta",

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AU - Sanphanya, Kingkan

AU - Wattanapitayakul, Suvara K.

AU - Phowichit, Suwadee

AU - Fokin, Valery V.

AU - Vajragupta, Opa

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AB - 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 IC50 against 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.

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10.1016/j.bmcl.2013.03.042