NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models.
NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models.
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NVP-AUY922：一种小分子 HSP90 抑制剂，在临床前乳腺癌模型中具有有效的抗肿瘤活性。
DOI：
10.1186/bcr1996
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Chène P
中科院分区：
文献类型：
--
作者：
Jensen MR;Schoepfer J;Radimerski T;Massey A;Guy CT;Brueggen J;Quadt C;Buckler A;Cozens R;Drysdale MJ;Garcia-Echeverria C;Chène P
热休克蛋白90（Heat shock protein 90，HSP 90）是一种多分子伴侣复合物，参与了大量客户蛋白的翻译后折叠，其中许多在肿瘤发生中起重要作用。HSP 90是近年来出现的一个有前途的新的抗癌治疗靶点。在一组乳腺癌细胞系和患者来源的人乳腺肿瘤中确定了使细胞数量减少50%（GI 50值）所需的HSP 90抑制剂NVP-AUY 922的浓度。为了研究化合物在体内的性质，在BT-474乳腺癌异种移植模型中建立了药代动力学特征、抗肿瘤作用和给药方案。通过免疫组织化学、Western印迹分析和免疫沉淀，在细胞培养和乳腺癌异种移植物中研究了对HSP 90-p23复合物、客户蛋白降解和热休克反应的影响。我们表明，新型小分子HSP 90抑制剂NVP-AUY 922有效抑制人乳腺癌细胞系的增殖，GI 50值在3至126 nM范围内。NVP-AUY 922诱导增殖抑制，同时HSP 70上调和客户蛋白耗尽-HSP 90抑制的标志。将NVP-AUY 922静脉内急性施用至携带皮下BT-474乳腺肿瘤的无胸腺小鼠（30 mg/kg）导致药物水平超过细胞GI 50值的1，000倍，持续约2天。当化合物每周给药一次时，观察到显著的生长抑制和良好的耐受性。治疗效果与药效学标志物的变化一致，包括HSP 90-p23解离、ERBB 2和P-AKT降低以及HSP 70蛋白水平升高。NVP-AUY 922是一种有效的小分子HSP 90抑制剂，在细胞和体内环境中对乳腺癌细胞显示出显著的活性。基于其作用机制、临床前活性特征、耐受性和药物特性，该化合物最近已进入临床I期乳腺癌试验。
Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies. The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation. We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion – hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels. NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials.
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作者：
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