2. Academic Validation
  3. Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach

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

  • Bioorg Med Chem Lett. 2013 May 15;23(10):2962-7. doi: 10.1016/j.bmcl.2013.03.042.
Kingkan Sanphanya 1,  Suvara K Wattanapitayakul,  Suwadee Phowichit,  Valery V Fokin,  Opa Vajragupta
Affiliations

Affiliation

  • 1 Excellent Center for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Rd, Bangkok 10400, Thailand.
PMID: 23562241 DOI: 10.1016/j.bmcl.2013.03.042
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 0.56μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3μM, 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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