title: Structure-activity relationships of benzbromarone metabolites and derivatives as EYA inhibitory anti-angiogenic agents.
abstract: The tyrosine phosphatase activity of the phosphatase-transactivator protein Eyes Absent (EYA) is angiogenic through its roles in endothelial cell migration and tube formation. Benzbromarone, a known anti-gout agent, was previously identified as an inhibitor of EYA with anti-angiogenic properties. Here we show that the major metabolite of BBR, 6-hydroxy benzbromarone, is a significantly more potent inhibitor of cell migration, tubulogenesis and angiogenic sprouting. In contrast, other postulated metabolites of BBR such as 5-hydroxy benzbromaorne and 1'-hydroxy benzbromarone are less potent inhibitors of EYA tyrosine phosphatase activity as well as being less effective in cellular assays for endothelial cell migration and angiogenesis. Longer substituents at the 2 position of the benzofuran ring promoted EYA3 binding and inhibition, but were less effective in cellular assays, likely reflecting non-specific protein binding and a resulting reduction in free, bio-available inhibitor. The observed potency of 6-hydroxy benzbromarone is relevant in the context of the potential re-purposing of benzbromarone and its derivatives as anti-angiogenic agents. 6-hydroxy benzbromarone represents a metabolite with a longer half-life and greater pharmacological potency than the parent compound, suggesting that biotransformation of benzbromarone could contribute to its therapeutic activity.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Ram Naresh
authors.initials: RN
authors.lastname: Pandey
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Tim Sen
authors.initials: TS
authors.lastname: Wang
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tadjuidje
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: McDonald
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001553:Benzbromarone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C085923:6-hydroxybenzbromarone; D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; D001553:Benzbromarone; C540714:EYA3 protein, human; D017027:Protein Tyrosine Phosphatases