title: Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents.
abstract: A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.
authors.affiliation: Shire BioChem, Inc., Laval, Quebec, Canada.
authors.forename: Henriette
authors.initials: H
authors.lastname: Gourdeau
authors.forename: Lorraine
authors.initials: L
authors.lastname: Leblond
authors.forename: Bettina
authors.initials: B
authors.lastname: Hamelin
authors.forename: Clemence
authors.initials: C
authors.lastname: Desputeau
authors.forename: Kelly
authors.initials: K
authors.lastname: Dong
authors.forename: Irenej
authors.initials: I
authors.lastname: Kianicka
authors.forename: Dominique
authors.initials: D
authors.lastname: Custeau
authors.forename: Chantal
authors.initials: C
authors.lastname: Boudreau
authors.forename: Lilianne
authors.initials: L
authors.lastname: Geerts
authors.forename: Sui-Xiong
authors.initials: SX
authors.lastname: Cai
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Denis
authors.initials: D
authors.lastname: Labrecque
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
mesh_terms: D000586:Amination; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001578:Benzopyrans / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001966:Bromine / Q000737:chemistry; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009336:Necrosis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001578:Benzopyrans; D001966:Bromine