1. Academic Validation
  2. 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. s-kawano@hhc.eisai.co.jp.
  • 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. kishi@chemistry.harvard.edu.
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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