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 | |
| 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
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach. / Sanphanya, Kingkan; Wattanapitayakul, Suvara K.; Phowichit, Suwadee; Fokin, Valery V.; Vajragupta, Opa.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 10, 15.05.2013, p. 2962-2967.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
AU - Sanphanya, Kingkan
AU - Wattanapitayakul, Suvara K.
AU - Phowichit, Suwadee
AU - Fokin, Valery V.
AU - Vajragupta, Opa
PY - 2013/5/15
Y1 - 2013/5/15
N2 - 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.
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.
KW - VEGFR-2 KDR VEGFR-2 inhibitor Molecular modeling Antiangiogenesis 1,4-Disubstituted 1,2,3-triazoles CuAAC reaction
UR - http://www.scopus.com/inward/record.url?scp=84876669366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876669366&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2013.03.042
DO - 10.1016/j.bmcl.2013.03.042
M3 - Article
VL - 23
SP - 2962
EP - 2967
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 10
ER -