2. Academic Validation
  3. Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors

Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors

  • Bioorg Med Chem. 2014 Jan 15;22(2):892-905. doi: 10.1016/j.bmc.2013.11.036.
Atsushi Suda 1,  Ken-ichi Kawasaki 2,  Susumu Komiyama 2,  Yoshiaki Isshiki 2,  Dong-Oh Yoon 3,  Sung-Jin Kim 3,  Young-Jun Na 3,  Kiyoshi Hasegawa 2,  Takaaki A Fukami 2,  Shigeo Sato 2,  Takaaki Miura 2,  Naomi Ono 2,  Toshikazu Yamazaki 2,  Ryoichi Saitoh 2,  Nobuo Shimma 2,  Yasuhiko Shiratori 2,  Takuo Tsukuda 2
Affiliations

Affiliations

  • 1 Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Electronic address: sudaats@chugai-pharm.co.jp.
  • 2 Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
  • 3 Discovery Research Center, C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, Republic of Korea.
PMID: 24369839 DOI: 10.1016/j.bmc.2013.11.036
Abstract

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (HSP90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural HSP90 Inhibitor geldanamycin with HSP90. We optimized affinity to HSP90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd=0.52nM) and strong in vitro cell growth inhibition against human Cancer cell lines (HCT116 IC50=0.098μM, NCI-N87 IC50=0.066μM) and also displayed high oral bioavailability in mice (F=44.0%) and potent antitumor efficacy in a human NCI-N87 gastric Cancer xenograft model (tumor growth inhibition=136%).

Keywords

Antitumor agent; Hsp90 inhibitor; Lead optimization; Structure-based drug design.

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