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
  • 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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