2. Academic Validation
  3. Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors

Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors

  • Bioorg Med Chem. 2014 Oct 1;22(19):5513-29. doi: 10.1016/j.bmc.2014.07.020.
Satoshi Nagao 1,  Yoshinobu Yamane 2,  Setsuo Funasaka 2,  Keigo Tanaka 2,  Kazuki Miyazaki 2,  Yoshihiko Kotake 2,  Jun-ichi Kamata 2,  Saori Watanabe-Miyano 2,  Osamu Toyama 2,  Yoichi Ozawa 2,  Yoshiharu Mizui 3,  Kiyoshi Okamoto 2,  Daisuke Ito 2
Affiliations

Affiliations

  • 1 Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. Electronic address: [email protected].
  • 2 Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
  • 3 Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan; H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA.
PMID: 25139751 DOI: 10.1016/j.bmc.2014.07.020
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.

Keywords

Cancer; Hypoxia; Hypoxia-inducible factor-1; Inhibitor; Small molecule; Structure–activity relationships.

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