Hsp90 molecular chaperone inhibitors: are we there yet?
Hsp90 molecular chaperone inhibitors: are we there yet?
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DOI：
10.1158/1078-0432.ccr-11-1000
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Workman P
中科院分区：
文献类型：
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作者：
Neckers L;Workman P
热休克蛋白（Heat shock protein，Hsp）90是一种ATP依赖的分子伴侣，可被恶性肿瘤细胞利用，以支持激活的癌蛋白，包括许多与癌症相关的激酶和转录因子，并且是致癌转化所必需的。最初人们对Hsp 90抑制剂持怀疑态度，但现在制药行业正在积极研究，已有17种药物进入临床试验。使用天然产物格尔德霉素和根赤霉素建立了Hsp 90的可药用性，所述天然产物模拟在伴侣蛋白的N-末端核苷酸结合口袋中采用的不寻常的ATP结构，并引起ATP结合/水解的有效和选择性阻断，抑制伴侣蛋白功能，消耗致癌客户，并显示抗肿瘤活性。这些天然产物的临床前数据提高了对Hsp 90作为药物靶点的兴趣，并且17-烯丙基氨基-17-脱甲氧基格尔德霉素（17-AAG，tanespimycin）已证明在HER 2+乳腺癌中具有临床活性（如RECIST标准所定义）。来自不同化学型的许多优化的合成小分子Hsp 90抑制剂现在处于临床试验中。本文综述了热休克蛋白90抑制剂的发现和发展，并对其未来的潜力进行了评估。在基础生物学和围绕Hsp 90的转译药物开发方面，通过使用Hsp 90抑制剂作为化学探针，已经从经验中获得了重要的学习。成功可能在于治疗对特定驱动致癌基因产物成瘾的癌症，如HER 2，ALK，EGFR和BRAF，这些是敏感的Hsp 90客户，以及恶性肿瘤，特别是多发性骨髓瘤，其中缓冲蛋白毒性应激对生存至关重要。我们讨论了提高Hsp 90抑制剂有效性的方法，并强调了新的分子伴侣和应激反应途径靶点，包括HSF 1和Hsp 70。
Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Hsp90’s druggability was established using the natural products geldanamycin and radicicol which mimic the unusual ATP structure adopted in the chaperone’s N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and demonstrate antitumor activity. Preclinical data with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has demonstrated clinical activity (as defined by RECIST criteria) in HER2+ breast cancer. Many optimized synthetic small molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. We review the discovery and development of Hsp90 inhibitors and assess their future potential. There has been significant learning from experience in both the basic biology and the translational drug development around Hsp90, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers addicted to particular driver oncogene products, such as HER2, ALK, EGFR and BRAF, that are sensitive Hsp90 clients, as well as in malignancies, especially multiple myeloma, where buffering of proteotoxic stress is critical for survival. We discuss approaches to enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress response pathway targets, including HSF1 and Hsp70.