Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Department of Medicinal Chemistry, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
School of Pharmacology, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Molecules. 2020 Oct 28;25(21):4991. doi: 10.3390/molecules25214991.
With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (, and ) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids , and exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.
目前已有 5 种组蛋白去乙酰化酶（HDAC）抑制剂获批用于癌症治疗，而靶向 HDAC 的蛋白水解靶向嵌合体（PROTAC）作为一种替代策略，正在成为 HDAC 靶向治疗干预的新兴方法。在此，我们设计、合成并对基于苯丁抑制素的三种羟肟酸（、和）进行了生物学评估，以观察它们是否可以通过招募细胞凋亡抑制蛋白 1（cIAP1）E3 泛素连接酶来作为 HDAC 降解剂发挥作用。在这三种化合物中，苯丁抑制素-SAHA 杂合体表现出与已批准的 HDAC 抑制剂 SAHA 相当甚至更强大的 HDAC1、HDAC6 和 HDAC8 抑制活性。值得注意的是，尽管在 6 小时的治疗后不能导致细胞内 HDAC 降解，但在 24 小时的治疗后，它可以显著降低细胞内 HDAC1、HDAC6 和 HDAC8 的水平。有趣的是，这种类似的现象也在 HDAC 抑制剂 SAHA 中观察到。与蛋白酶体抑制剂硼替佐米共同处理不能逆转和 SAHA 的 HDAC 降低作用，这证实了它们的 HDAC 降低作用不是由于蛋白质降解引起的。此外，基于苯丁抑制素的三种羟肟酸、和都表现出比已批准的 APN 抑制剂苯丁抑制素更强的氨肽酶 N（APN，CD13）抑制活性，这转化为它们具有更好的抗血管生成活性。总之，开发了一种新型的苯丁抑制素-SAHA 杂合体，它作为一种有效的 APN 和 HDAC 双重抑制剂发挥作用，而不是 PROTAC。
