Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers.
Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers.
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DOI：
10.1016/j.bbamcr.2011.10.008
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Chiosis G
中科院分区：
文献类型：
--
作者：
Jhaveri K;Taldone T;Modi S;Chiosis G
热休克蛋白90是一种ATP依赖的分子伴侣蛋白，它整合了多种致癌途径。因此，Hsp 90抑制是一种有前途的抗癌策略。几种通过结合其N-末端ATP口袋作用于Hsp 90的抑制剂已进入临床评价。稳健的临床前数据表明在多种癌症类型中具有抗肿瘤活性。在临床上，在黑色素瘤、急性髓性白血病、去势难治性前列腺癌、非小细胞肺癌和多发性骨髓瘤中已经证明了令人鼓舞的结果。在乳腺癌中，第一代Hsp 90抑制剂与曲妥珠单抗联合治疗主要在人表皮生长因子受体2（HER 2）+转移性乳腺癌中证实了概念验证。目前有许多第二代Hsp 90抑制剂正在研究中。然而，迄今为止，没有FDA批准的Hsp 90抑制剂，也没有标准化的测定来确定Hsp 90抑制。本文根据第一代和第二代Hsp 90抑制剂的化学分类和临床开发阶段，对第一代和第二代Hsp 90抑制剂的研究现状进行了综述。它还讨论了目前在临床上实施的药效学测定以及其他新的策略，旨在提高Hsp 90抑制剂的有效性。最终，这些努力将有助于最大限度地发挥这类代理的全部潜力。
Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents.
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HSP90 抑制剂可阻断曲妥珠单抗耐药肿瘤中的 p95-HER2 信号传导并抑制其生长。
影响因子：
8
作者：
Chandarlapaty, S.;Scaltriti, M.;Angelini, P.;Ye, Q.;Guzman, M.;Hudis, C. A.;Norton, L.;Solit, D. B.;Arribas, J.;Baselga, J.;Rosen, N.
通讯作者：
Rosen, N.
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
影响因子：
11.5
作者：
Eiseman, Julie L.;Guo, Jianxia;Egorin, Merrill J.
通讯作者：
Egorin, Merrill J.
影响因子：
2.6
作者：
Dakappagari, Naveen;Neely, Laura;Zhang, Hong
通讯作者：
Zhang, Hong
影响因子：
11.2
作者：
Eccles, Suzanne A.;Massey, Andy;Workman, Paul
通讯作者：
Workman, Paul