微管蛋白脱乙酰酶 Sirtuin 2 (Sirt2) 和组蛋白脱乙酰酶 6 (HDAC6) 的失调与癌症和神经退行性疾病的发病机制有关，因此这两种酶成为药物干预的有希望的靶标。在此，我们报告了一流的双 Sirt2/HDAC6 抑制剂的设计、合成和生物学表征，作为微管蛋白脱乙酰化双重抑制的分子工具。使用生化体外测定和基于细胞的靶点接合方法，我们确定 Mz325 (33) 是两种靶酶的有效且选择性抑制剂。 Sirt2 和 HDAC6 与 33 组成复合物的 X 射线晶体结构进一步证实了这两个靶点的抑制作用。在卵巢癌细胞中，与未结合的 Sirt2 和 HDAC6 抑制剂单独或联合治疗相比，33 对细胞活力产生了增强的影响。因此，我们的 Sirt2/HDAC6 双重抑制剂是研究微管蛋白脱乙酰化双重抑制的后果和治疗潜力的重要新工具。

Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.