Drugging the cancer chaperone HSP90 combinatorial therapeutic exploitation of oncogene addiction and tumor stress
Drugging the cancer chaperone HSP90 combinatorial therapeutic exploitation of oncogene addiction and tumor stress
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DOI：
10.1196/annals.1391.012
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Rosen, Neal
中科院分区：
文献类型：
--
作者：
Workman, Paul;Burrows, Francis;Rosen, Neal
分子伴侣HSP 90已成为一个令人兴奋的癌症治疗靶点。我们回顾了热休克蛋白90抑制剂的潜在优势，特别是多个致癌的“客户”蛋白的同时组合耗尽，导致许多致癌途径的封锁和所有的恶性肿瘤的标志性病理特征的拮抗作用。癌症的选择性是通过利用癌症的“依赖性”来实现的，包括癌基因成瘾和恶性细胞的应激状态。HSP 90抑制剂的多重下游效应应使耐药性的发展比具有更有限作用的药物更困难。我们回顾了各种类型的HSP 90抑制剂，已开发的，包括天然产物格尔德霉素和根赤霉素，也嘌呤支架和吡唑/异恶唑类的合成小分子抑制剂。第一种HSP 90药物，格尔德霉素类似物17-AAG，已经提供了在患者中以良好耐受剂量抑制HSP 90的概念证明，并且已经看到了治疗活性。其他抑制剂在临床前和临床开发中显示出前景。讨论了HSP 90抑制剂的机遇和挑战，包括与其他药物联合使用。目前大多数HSP 90抑制剂通过阻断伴侣功能所需的基本核苷酸结合和ATP酶活性来起作用。潜在的新方法进行了讨论，例如，干扰cochaperone的结合和功能的superchaperone复合物。描述了与HSP 90抑制剂一起使用的生物标志物。
The molecular chaperone HSP90 has emerged as an exciting target for cancer treatment. We review the potential advantages of HSP90 inhibitors, particularly the simultaneous combinatorial depletion of multiple oncogenic "client" proteins, leading to blockade of many cancer-causing pathways and the antagonism of all of the hallmark pathological traits of malignancy. Cancer selectivity is achieved by exploiting cancer "dependencies," including oncogene addiction and the stressed state of malignant cells. The multiple downstream effects of HSP90 inhibitors should make the development of resistance more difficult than with agents having more restricted effects. We review the various classes of HSP90 inhibitor that have been developed, including the natural products geldanamycin and radicicol and also the purine scaffold and pyrazole/isoxazole class of synthetic small molecule inhibitors. A first-in-class HSP90 drug, the geldanamycin analog 17-AAG, has provided proof of concept for HSP90 inhibition in patients at well tolerated doses and therapeutic activity has been seen. Other inhibitors show promise in preclinical and clinical development. Opportunities and challenges for HSP90 inhibitors are discussed, including use in combination with other agents. Most of the current HSP90 inhibitors act by blocking the essential nucleotide binding and ATPase activity required for chaperone function. Potential new approaches are discussed, for example, interference with cochaperone binding and function in the superchaperone complex. Biomarkers for use with HSP90 inhibitors are described.