Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.

单胺氧化酶 A (MAO A) 和热休克蛋白 90 (HSP90) 抑制剂已被证明可以减缓胶质母细胞瘤 (GBM) 和其他癌症的进展。本研究设计合成了一系列MAO A/HSP90双重抑制剂，希望开发出更有效的GBM治疗方法。化合物4-b和4-c是异丙基间苯二酚（HSP90抑制剂的药效团）与氯吉林（MAO A抑制剂）的苯基通过被甲基（ 4-b ）或乙基（ 4-c ）基团取代的叔酰胺键的缀合物， 分别。它们抑制 MAO A 活性、HSP90 结合以及 TMZ 敏感和耐药 GBM 细胞的生长。蛋白质印迹显示，与 MAO A 或 HSP90 抑制剂本身类似，它们增加了 HSP70 表达，表明 HSP90 功能降低，HER2 和磷酸-Akt 表达降低。这两种化合物都能降低 GL26 细胞中 IFN-γ 诱导的 PD-L1 表达，表明它们可以充当免疫检查点抑制剂。此外，他们还减少了 GL26 小鼠模型中的肿瘤生长。 NCI-60 分析表明它们还抑制结肠癌、白血病、非小细胞肺癌和其他癌症的生长。综上所述，这项研究表明 MAO A/HSP90 双重抑制剂4-b和4-c可以减少 GBM 和其他癌症的生长，并且它们具有抑制肿瘤免疫逃逸的潜力。