Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors |
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Authors: | Suda Atsushi Koyano Hiroshi Hayase Tadakatsu Hada Kihito Kawasaki Ken-Ichi Komiyama Susumu Hasegawa Kiyoshi Fukami Takaaki A Sato Shigeo Miura Takaaki Ono Naomi Yamazaki Toshikazu Saitoh Ryoichi Shimma Nobuo Shiratori Yasuhiko Tsukuda Takuo |
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Institution: | Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sudaats@chugai-pharm.co.jp |
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Abstract: | Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). CH5164840 displayed high oral bioavailability in mice (F=70.8%) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition=83%). |
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