Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
Curr Mol Med. 2012 Nov 1;12(9):1108-24. doi: 10.2174/156652412803306657.
Since the identification of the first HSP90 inhibitor almost two decades ago, there has been substantial progress made in the development of potent and selective molecules that inhibit this chaperone and that have anticancer activity. In turn, these compounds have been invaluable for probing how HSP90 supports the profound changes in cellular physiology that characterize the malignant state. Unfortunately, when used as single agents HSP90 inhibitors have demonstrated disappointing activity against advanced cancers in most of the clinical trials reported to date. This problem may be due to the major pharmacological liabilities of the first-generation HSP90 inhibitors that have been most extensively studied. We suggest, however, that it may well be intrinsic to the target itself. Systemically tolerable exposure to HSP90 inhibitors may not be highly cytotoxic for the majority of common clinical cancers. Instead, HSP90 inhibitors might better be used to enhance the activity of other antineoplastic agents while simultaneously reducing the capacity of tumors to adapt and evolve drug resistance; the overall result being more durable disease control. This review will focus on these fundamental issues with the goal of suggesting ways to make the clinical development of HSP90 inhibitors become less empiric and ultimately more successful.
自近二十年前发现第一个 HSP90 抑制剂以来，在开发强效和选择性抑制该伴侣蛋白并具有抗癌活性的分子方面取得了实质性进展。反过来，这些化合物对于探究 HSP90 如何支持恶性状态下细胞生理学的深刻变化非常有价值。不幸的是，在大多数已报告的临床试验中，当作为单一药物使用时，HSP90 抑制剂对晚期癌症的活性令人失望。这个问题可能是由于已被广泛研究的第一代 HSP90 抑制剂的主要药理学局限性所致。然而，我们认为，这可能是该靶本身固有的。对 HSP90 抑制剂的系统可耐受暴露对于大多数常见临床癌症可能不会具有高度细胞毒性。相反，HSP90 抑制剂可能更适合用于增强其他抗肿瘤药物的活性，同时降低肿瘤适应和产生耐药性的能力；总体结果是更持久的疾病控制。本综述将重点讨论这些基本问题，旨在提出使 HSP90 抑制剂的临床开发变得不那么经验主义并最终更成功的方法。
