Introduction

The tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability.

Objectives

We propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity.

Methods

A hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo.

Results

Compound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic reduction of immunosuppressive regulatory T cells. Delightfully, a cocktail treatment of compound 17 and anti-PD-1 antibodies demonstrated synergistic efficacy to eliminate solid tumors with 83.9% of tumor growth inhibition.

Conclusion

In summary, the impressive activity profile of compound 17, as an effective anticancer agent and a potential immunosensitizer, forecasts the application of HDAC6/HSP90 dual inhibitory strategy to overcome the immunosuppressive tumor microenvironment.

中文翻译：

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合理设计可合成处理的 HDAC6/HSP90 双重抑制剂以破坏免疫抑制肿瘤微环境

介绍

肿瘤微环境主要充斥着免疫抑制细胞和抑制性细胞因子，导致有效免疫细胞无法浸润和识别肿瘤，甚至丧失抗癌能力。

目标

我们提出了一种新的 HDAC6/HSP90 双重抑制策略以及一种化学免疫治疗剂，它不仅可以杀死肿瘤细胞，还可以破坏肿瘤微环境并增强抗癌免疫力。

方法

利用混合支架构建方法提供一系列合理设计的基于间苯二酚的异羟肟酸酯作为双选择性 HDAC6/HSP90 抑制剂。药物设计活动从片段招募过程开始，以确定经过验证的结构单元以抑制 HDAC6 和 HSP90，然后通过高效简便的多步合成路线将它们安装在灵活的 HDAC 抑制模板中。随后的评估通过体外和体内的分子和生物学分析确定了一种非常有效的选择性 HDAC6/HSP90 双重抑制剂（化合物17 ） 。

结果

化合物17不仅表现出对癌细胞的直接细胞毒性，而且通过抑制 STAT1 通路和癌基因蛋白（Src、AKT、Rb 和 FAK）的降解，下调肿瘤中免疫检查点（PD-L1 和 IDO）的表达，导致in体内肿瘤生长抑制。这些多重效应使效应 T 细胞能够大量浸润到肿瘤区域并释放颗粒酶 B 来杀死癌细胞。此外，化合物17还减少了正常细胞的 TGF-β 分泌，导致免疫抑制调节性 T 细胞的全身减少。令人高兴的是，化合物17的鸡尾酒疗法和抗 PD-1 抗体显示出消除实体瘤的协同功效，抑制了 83.9% 的肿瘤生长。

结论

总之，作为一种有效的抗癌剂和潜在的免疫增敏剂，化合物17令人印象深刻的活性特征预测了 HDAC6/HSP90 双重抑制策略在克服免疫抑制性肿瘤微环境中的应用。