title: Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach.
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.
authors.affiliation: Excellent Center for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Rd, Bangkok 10400, Thailand.
authors.forename: Kingkan
authors.initials: K
authors.lastname: Sanphanya
authors.forename: Suvara K
authors.initials: SK
authors.lastname: Wattanapitayakul
authors.forename: Suwadee
authors.initials: S
authors.lastname: Phowichit
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C584461:VH02 compound; D040301:Vascular Endothelial Growth Factor Receptor-2
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