聚焦17-AAG作为Hsp90抑制剂用于分子靶向癌症治疗。,Chemical Biology & Drug Design

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聚焦17-AAG作为Hsp90抑制剂用于分子靶向癌症治疗。
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2019-02-14 , DOI: 10.1111/cbdd.13486
Sona Talaei _{1,

2} , Hassan Mellatyar _{1,

2} , Asadollah Asadi ₃ , Abolfazl Akbarzadeh ₄ , Roghayeh Sheervalilou ₁ , Nosratollah Zarghami _{1,

2,

5}

Affiliation

Hsp90是一种普遍存在的伴侣蛋白，在与癌细胞的进程和存活有关的客户蛋白质的组织和成熟中具有重要作用。Hsp90功能通过其客体蛋白的降解而受到抑制，可以影响多种致癌途径。这使得Hsp90成为癌症治疗的治疗靶标。17-烯丙基氨基-17-去甲氧基-格尔德霉素（17-AAG）是一种有效的Hsp90抑制剂，可与Hsp90结合并抑制其伴侣功能，从而导致Hsp90的客户蛋白质降解。17-AAG作为单一药物或与其他抗癌药物联合用于多种人类癌症的临床前研究已有数项。来自临床试验各个阶段的数据表明，可以以具有轻度毒性的生物活性剂量安全地给予17-AAG。尽管17-AAG具有合适的药理作用，但其低水溶性和高肝毒性可能会极大地限制其临床应用。基于纳米材料的药物递送载体可以克服这些缺点。在本文中，我们综述了17-AAG作为单一药物并与其他抗癌药物联合使用的临床前和临床研究。此外，我们强调了使用纳米载体和纳米组合疗法改善17-AAG治疗效果的潜力。

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Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment.

Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins. There have been several preclinical studies of 17-AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases of clinical trials show that 17-AAG can be given safely at biologically active dosages with mild toxicity. Even though 17-AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials-based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17-AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17-AAG.

更新日期：2019-02-14

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