title: Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors.
abstract: Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. Electronic address: s-nagao@hhc.eisai.co.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yamane
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Setsuo
authors.initials: S
authors.lastname: Funasaka
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kotake
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kamata
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Watanabe-Miyano
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Toyama
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan; H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Mizui
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D051793:Hypoxia-Inducible Factor 1; D054852:Small Molecule Libraries; C034595:benzanilide
keywords: Cancer; Hypoxia; Hypoxia-inducible factor-1; Inhibitor; Small molecule; Structure–activity relationships