ABSTRACT
The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches.
Subject(s)
Angiogenesis Inhibitors/chemistry , Antibodies, Monoclonal/chemistry , Vascular Endothelial Growth Factor Receptor-2/chemistry , Amino Acid Motifs , Amino Acid Sequence , Antibodies, Monoclonal, Humanized , Antibody Specificity , Binding Sites, Antibody , Crystallography, X-Ray , Enzyme-Linked Immunosorbent Assay , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Binding , Protein Structure, Quaternary , Protein Structure, Tertiary , Vascular Endothelial Growth Factor Receptor-2/genetics , RamucirumabABSTRACT
A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice.
Subject(s)
Benzamides/pharmacology , Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , In Vitro Techniques , Mice , Models, Animal , Molecular Sequence Data , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model.
