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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 10; pp. 2962 - 2967
• Main Authors: Sanphanya, Kingkan, Wattanapitayakul, Suvara K., Phowichit, Suwadee, Fokin, Valery V., Vajragupta, Opa
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.05.2013; Elsevier
• Subjects: 1,4-Disubstituted 1,2,3-triazoles; Antiangiogenesis; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; binding capacity; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CuAAC reaction; cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; human umbilical vein endothelial cells; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; inhibitory concentration 50; KDR; Life Sciences & Biomedicine; MCF-7 Cells; Models, Molecular; Molecular modeling; Molecular Structure; Pharmacology & Pharmacy; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; triazoles; vascular endothelial growth factor receptor-2; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2; VEGFR-2 inhibitor; CuAAC reaction; VEGFR-2; Molecular modeling; Antiangiogenesis; KDR; VEGFR-2 inhibitor; 1,4-Disubstituted 1,2,3-triazoles; DESIGN; SERIES; ANGIOGENESIS; STRATEGY; CANCER; DISCOVERY; POTENT; RECEPTOR TYROSINE KINASES; TARGETS; ENDOTHELIAL GROWTH-FACTOR
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.03.042

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.