2. Academic Validation
  3. A landmark in drug discovery based on complex natural product synthesis

A landmark in drug discovery based on complex natural product synthesis

  • Sci Rep. 2019 Jun 17;9(1):8656. doi: 10.1038/s41598-019-45001-9.
Satoshi Kawano 1,  Ken Ito 2,  Kenzo Yahata 3,  Kazunobu Kira 2,  Takanori Abe 2,  Tsuyoshi Akagi 2,  Makoto Asano 2,  Kentaro Iso 2,  Yuki Sato 2,  Fumiyoshi Matsuura 4,  Isao Ohashi 2,  Yasunobu Matsumoto 2,  Minetaka Isomura 2,  Takeo Sasaki 2,  Takashi Fukuyama 2,  Yusuke Miyashita 5,  Yosuke Kaburagi 2,  Akira Yokoi 2,  Osamu Asano 2,  Takashi Owa 6,  Yoshito Kishi 7
Affiliations

Affiliations

  • 1 Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan. [email protected].
  • 2 Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
  • 3 Harvard University, Cambridge, Massachusetts, USA.
  • 4 Eisai Co., Ltd., Koishikawa, Bunkyo-ku, Tokyo, Japan.
  • 5 Eisai Co., Ltd., Sunayama, Kamisu-shi, Ibaraki, Japan.
  • 6 Eisai Inc., Woodcliff Lake, New Jersey, USA.
  • 7 Harvard University, Cambridge, Massachusetts, USA. [email protected].
PMID: 31209263 DOI: 10.1038/s41598-019-45001-9
Abstract

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex Natural Products.

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