Ganetespib: research and clinical development.
Ganetespib: research and clinical development.
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DOI：
10.2147/ott.s65804
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发表时间：
2015
影响因子：
4
通讯作者：
Modi S
中科院分区：
文献类型：
--
作者：
Jhaveri K;Modi S
在应激条件下，热休克蛋白 90 (HSP90) 分子伴侣可通过泛素-蛋白酶体途径保护细胞蛋白（客户蛋白）免遭降解。 HSP90 表达在癌症中上调，这有助于增殖增加、细胞凋亡减少以及通过保护其客户蛋白（包括人表皮生长因子受体 2、间变性淋巴瘤激酶、雄激素受体、雌激素受体、Akt、Raf-1、细胞周期蛋白和 B 细胞淋巴瘤 2 等）维持转移潜力的恶性表型。因此，抑制 HSP90 会导致其许多客户同时降解，从而破坏多个致癌信号级联。这引发了人们对开发 HSP90 抑制剂作为创新抗癌策略的巨大兴趣。基于临床前研究中大量令人信服的数据，多种HSP90抑制剂已进入临床测试。然而，尽管迄今为止报道了巨大的前景和抗癌活性，但正在开发的 HSP90 抑制剂尚未被批准用于癌症治疗，并且此类药物的全部潜力尚未实现。本文对 Ganetespib 进行了综述，Ganetespib 是一种小分子 HSP90 抑制剂，目前正在评估与其他治疗药物联合用于多种癌症类型，希望进一步增强其疗效并克服耐药性。根据我们目前对复杂 HSP90 机制的了解，结合这些关键临床试验的新数据，ganetespib 有潜力成为第一个被批准作为新抗癌疗法的 HSP90 抑制剂。
Under stressful conditions, the heat shock protein 90 (HSP90) molecular chaperone protects cellular proteins (client proteins) from degradation via the ubiquitin-proteasome pathway. HSP90 expression is upregulated in cancers, and this contributes to the malignant phenotype of increased proliferation and decreased apoptosis and maintenance of metastatic potential via conservation of its client proteins, including human epidermal growth factor receptor 2, anaplastic lymphoma kinase, androgen receptor, estrogen receptor, Akt, Raf-1, cell cycle proteins, and B-cell lymphoma 2 among others. Hence, inhibition of HSP90 leads to the simultaneous degradation of its many clients, thereby disrupting multiple oncogenic signaling cascades. This has sparked tremendous interest in the development of HSP90 inhibitors as an innovative anticancer strategy. Based on the wealth of compelling data from preclinical studies, a number of HSP90 inhibitors have entered into clinical testing. However, despite enormous promise and anticancer activity reported to date, none of the HSP90 inhibitors in development has been approved for cancer therapy, and the full potential of this class of agents is yet to be realized. This article provides a review on ganetespib, a small molecule HSP90 inhibitor that is currently under evaluation in a broad range of cancer types in combination with other therapeutic agents with the hope of further enhancing its efficacy and overcoming drug resistance. Based on our current understanding of the complex HSP90 machinery combined with the emerging data from these key clinical trials, ganetespib has the potential to be the first-in-class HSP90 inhibitor to be approved as a new anticancer therapy.