新型Hsp90抑制剂2-氨基-6-(1H,3H-苯并[de]异色烯-6-基)-1,3,5-三嗪的设计与合成
Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.
作者信息
Suda Atsushi, Kawasaki Ken-ichi, Komiyama Susumu, Isshiki Yoshiaki, Yoon Dong-Oh, Kim Sung-Jin, Na Young-Jun, Hasegawa Kiyoshi, Fukami Takaaki A, Sato Shigeo, Miura Takaaki, Ono Naomi, Yamazaki Toshikazu, Saitoh Ryoichi, Shimma Nobuo, Shiratori Yasuhiko, Tsukuda Takuo
机构信息
Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
出版信息
Bioorg Med Chem. 2014 Jan 15;22(2):892-905. doi: 10.1016/j.bmc.2013.11.036. Epub 2013 Nov 25.
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%).
描述了一系列新型的带有三环部分的2-氨基-1,3,5-三嗪作为热休克蛋白90（Hsp90）抑制剂。利用先导化合物CH5015765和天然Hsp90抑制剂格尔德霉素与Hsp90的X射线共晶体结构进行分子设计。我们优化了抑制剂对Hsp90的亲和力、体外细胞生长抑制活性、水溶性和肝微粒体稳定性，并鉴定出CH5138303。该化合物对N端Hsp90α显示出高结合亲和力（Kd = 0.52 nM），对人癌细胞系具有强体外细胞生长抑制作用（HCT116 IC50 = 0.098 μM，NCI-N87 IC50 = 0.066 μM），并且在小鼠中也显示出高口服生物利用度（F = 44.0%）以及在人NCI-N87胃癌异种移植模型中具有强效抗肿瘤功效（肿瘤生长抑制率 = 136%）。
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