Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin.

尽管已知组蛋白脱乙酰基酶（HDAC）抑制剂可抑制多种类型的癌细胞中的癌干细胞（CSC）群体，但尚不清楚哪种HDAC亚型和相应的机制有助于这种抗CSC活性。根据我们先前的发现，HDAC8通过靶向Notch1稳定性来调节三阴性乳腺癌（TNBC）细胞中的CSC，我们研究了相关途径，并发现HDAC3通过Akt /GSK3β途径增加β-catenin的表达与CSC稳态机制相关。 。因此，我们使用泛HDAC抑制剂AR-42（1）作为支架来开发HDAC3选择性抑制剂，并获得18和28的概念验证。。这两种衍生物在HDAC3抑制中表现出很高的效价和同工型选择性。同样重要的是，它们显示出通过下调β-catenin抑制TNBC细胞CSC亚群的体外和/或体内功效。