Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions
Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions
复制标题
开发热休克蛋白 (Hsp90) 抑制剂，通过 Hsp90-激酶相互作用对抗酪氨酸激酶抑制剂耐药性
DOI：
10.1021/acs.jmedchem.5b01106
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发表时间：
2016-06-23
影响因子：
7.3
通讯作者：
Zhang, Ao
中科院分区：
文献类型：
--
作者：
Wang, Meining;Shen, Aijun;Zhang, Ao
热休克蛋白90（Heat shock protein 90，Hsp 90）是一种广泛存在于所有致癌酪氨酸激酶中的分子伴侣。许多Hsp 90抑制剂，单独或组合，已显示出显着的抗肿瘤疗效对激酶阳性的幼稚和突变体模型。然而，这些抑制剂的临床试验是不成功的，由于不足的临床效益和非最佳的安全性。近年来，对Hsp 90-cochaperone-client复合物的研究取得了很大进展，这无疑将有助于理解Hsp 90与其客户之间的相互作用。与此同时，Hsp 90抑制剂已显示出对抗早期酪氨酸激酶抑制剂（TKI）引起的患者耐药的前景，至少有13种Hsp 90抑制剂正在临床上重新评估。在这方面，目前的观点的目标是总结的结构和功能的热休克蛋白90-伴侣-客户端复合物，分析的结构和功能的见解到热休克蛋白90客户端的相互作用，以解决一些现有的未解决的问题与热休克蛋白90抑制剂，并强调临床前和临床研究的热休克蛋白90抑制剂作为一种有效的治疗对酪氨酸激酶抑制剂的耐药性。
Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naive and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.