Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2012 Jan 1;18(1):64-76. doi: 10.1158/1078-0432.CCR-11-1000.
Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Investigators established Hsp90's druggability 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 show antitumor activity. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (especially multiple myeloma) in which buffering of proteotoxic stress is critical for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70.
热休克蛋白 90（Hsp90）是一种依赖于 ATP 的分子伴侣，恶性细胞利用它来支持激活的癌蛋白，包括许多与癌症相关的激酶和转录因子，它对致癌转化至关重要。最初人们对 Hsp90 抑制剂持怀疑态度，但现在制药行业正在积极研究 Hsp90 抑制剂，已有 17 种药物进入临床试验。研究人员使用 geldanamycin 和 radicicol 等天然产物来确定 Hsp90 的可药性，这两种天然产物模拟了伴侣蛋白 N 端核苷酸结合口袋中采用的不寻常的 ATP 结构，导致强烈而选择性地阻断 ATP 结合/水解，抑制伴侣蛋白功能，耗尽致癌客户，并显示抗肿瘤活性。这些天然产物获得的临床前数据提高了人们对 Hsp90 作为药物靶点的兴趣，并且 17-allylamino-17-demethoxygeldanamycin（17-AAG，tanespimycin）在 HER2+乳腺癌中显示出临床活性（根据实体瘤反应评估标准定义）。现在，许多来自不同化学类型的优化合成小分子 Hsp90 抑制剂正在临床试验中。在这里，我们回顾了 Hsp90 抑制剂的发现和开发，并评估了它们的潜力。从 Hsp90 的基础生物学研究以及涉及这种伴侣蛋白的转化药物开发中获得了重大经验教训，通过使用 Hsp90 抑制剂作为化学探针来增强。成功可能在于治疗对特定驱动癌基因产物（例如 HER2、ALK、EGFR 和 BRAF）上瘾的癌症，这些产物是敏感的 Hsp90 客户，以及缓冲蛋白毒性应激对生存至关重要的恶性肿瘤（尤其是多发性骨髓瘤）。我们讨论了增强 Hsp90 抑制剂有效性的方法，并强调了新的伴侣蛋白和应激反应途径靶点，包括 HSF1 和 Hsp70。
