Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects,Journal of Medicinal Chemistry

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Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-10 , DOI: 10.1021/acs.jmedchem.4c00966
Xinqi Liang ₁ , Ruixian Chen _{1,

2} , Chengdi Wang ₁ , Yuxi Wang _{1,

3} , Jifa Zhang _{1,

3}

Affiliation

Heat shock protein 90 (HSP90), a highly conserved member of the heat shock protein family, regulates various proteins and signaling pathways involved in cancer, making it a promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential in preclinical trials, with over 20 compounds advancing to clinical trials and showing promising results. However, the limited clinical efficacy and shared toxicity of these inhibitors restrict their further clinical use. Encouragingly, developing novel inhibitors using conventional medicinal chemistry approaches─such as selective inhibitors, dual inhibitors, protein–protein interaction inhibitors, and proteolysis-targeting chimeras─is expected to address these challenges. Notably, the selective inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize the structure, biological functions, and roles of HSP90 in cancer, analyze the clinical status of HSP90 inhibitors, and highlight the latest advancements in novel strategies, offering insights into their future development.

中文翻译：

针对 HSP90 的癌症治疗：当前进展和新兴前景

热休克蛋白90（HSP90）是热休克蛋白家族中高度保守的成员，调节与癌症相关的各种蛋白质和信号通路，使其成为癌症治疗的有希望的靶点。传统的 HSP90 抑制剂在临床前试验中已表现出显着的抗肿瘤潜力，已有 20 多种化合物进入临床试验并显示出可喜的结果。然而，这些抑制剂有限的临床疗效和共同的毒性限制了它们的进一步临床使用。令人鼓舞的是，使用传统药物化学方法开发新型抑制剂（例如选择性抑制剂、双重抑制剂、蛋白质-蛋白质相互作用抑制剂和蛋白水解靶向嵌合体）有望解决这些挑战。值得注意的是，选择性抑制剂TAS-116已成功上市。在本篇《展望》中，我们总结了HSP90的结构、生物学功能和在癌症中的作用，分析了HSP90抑制剂的临床状况，并重点介绍了新策略的最新进展，为其未来发展提供了见解。

更新日期：2024-09-10

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