Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents
Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents
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DOI：
10.1021/jm900230j
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发表时间：
2009-07-23
影响因子：
7.3
通讯作者：
Hall, Steven E.
中科院分区：
文献类型：
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作者：
Huang, Kenneth H.;Veal, James M.;Hall, Steven E.
通过无偏筛选，开发了一类新的热休克蛋白90（Hsp 90）抑制剂，以确定不同化合物库的蛋白质靶点。这些吲哚-4-酮和吲唑-4-酮衍生的2-氨基苯甲酰胺显示出对Hsp 90的强结合亲和力，并且优化的类似物在多种癌细胞系中表现出纳摩尔级的抗增殖活性。热休克蛋白70（Hsp 70）的诱导和特定的客户端蛋白降解的细胞处理的抑制剂支持Hsp 90抑制的作用机制。计算化学和X-射线晶体学分析选定的成员化合物清楚地定义了蛋白质抑制剂的相互作用，并协助类似物的设计。4-[6，6-二甲基-4-氧代-3-（三氟甲基）苯基]-2-甲基-3-氧代-4-氧代-1，4-二苯甲酰胺（三氟甲基）-4，5，6，7-四氢-1H-吲唑-1-基]-2-[（反式-4-羟基环己基）氨基]苯甲酰胺（SNX-2112，9）被鉴定为高度选择性和有效的（IC50 Her2 = 11 nM，HT-29 = 3 nM）;其前药氨基乙酸4-[2-氨基甲酰基-5-（6，6-二甲基-4-氧代-3-三氟甲基-4，5，6，7-四氢-吲唑-1-基）-苯基氨基]-环己基酯甲磺酸盐（SNX-5422，10）在广泛的异种移植肿瘤模型中是口服生物可利用的和有效的（例如，在HT-29模型中67%的生长延迟），并且现在处于多个I期临床试验中。
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC50 Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.