Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Bioorg Med Chem Lett. 2012 Jan 15;22(2):1136-41. doi: 10.1016/j.bmcl.2011.11.100. Epub 2011 Dec 1.
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%).
通过对 2-氨基-6-芳基三嗪衍生物（CH5015765）进行修饰，发现具有 2-氨基-6-芳基嘧啶部分的大环化合物是有效的热休克蛋白 90（Hsp90）抑制剂。我们采用大环结构作为新型抑制剂的骨架，以模拟格尔德霉素-Hsp90 的相互作用。在所鉴定的抑制剂中，CH5164840 对 N 端 Hsp90α 具有高结合亲和力（Kd=0.52nM），对人癌细胞系具有强的抗增殖活性（HCT116 IC50=0.15μM，NCI-N87 IC50=0.066μM）。CH5164840 在小鼠中具有较高的口服生物利用度（F=70.8%），并在 HCT116 人结直肠癌细胞异种移植模型中具有较强的抗肿瘤疗效（肿瘤生长抑制=83%）。
