title: Angiogenesis inhibitors identified by cell-based high-throughput screening: synthesis, structure-activity relationships and biological evaluation of 3-[(E)-styryl]benzamides that specifically inhibit endothelial cell proliferation.
abstract: Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) proliferation inhibitors from a cell-based high-throughput screening (HTS), we eliminated those compounds which showed cytotoxicity against HCT116 and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitory activity. Evaluations in human Calu-6 xenograft model delivered lead compound 1. Following extensive lead optimization and alteration of the scaffold we discovered 32f and 32g, which both inhibited the proliferation and tube formation of HUVEC without showing inhibitory activity against any of 25 kinases or cytotoxicity against either normal fibroblasts or 40 cancer cell lines. Upon oral administration, 32f and 32g had good pharmacokinetic profiles and potent antitumor activity and decreased microvessel density (MVD) in Calu-6 xenograft model. Combination therapy with a VEGFR inhibitor enhanced the in vivo efficacy. These results suggest that 32f and 32g may have potential for use in cancer treatment.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. hadakht@chugai-pharm.co.jp
authors.forename: Kihito
authors.initials: K
authors.lastname: Hada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suda
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Asoh
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.forename: Masami
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Shino
authors.initials: S
authors.lastname: Kuramoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koyano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D001593:Benzyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D001593:Benzyl Compounds; D010647:Phenyl Ethers; C572546:RO0123743; D013343:Styrenes