Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA.
Chem Biol Drug Des. 2013 Mar;81(3):334-42. doi: 10.1111/cbdd.12059.
Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.
Hes1 是一种主要受 Notch 信号通路调控的关键转录调节因子，最近的研究表明 Hes1 具有致癌和肿瘤抑制作用，具体取决于细胞类型。激活和抑制 Hes1 活性的小分子有望成为未来的抗癌化疗药物。我们利用基于细胞的双荧光素酶测定法，以高通量的方式鉴定 Hes1 表达的调节剂。在 HCT-116 结肠癌细胞系中进行了适度的筛选，鉴定并表征了两种小分子作为 Hes1 调节剂。化合物 3 诱导 Hes1 表达，并在肺类癌肿瘤细胞中表现出抗癌作用，在这种细胞类型中，上调的 Notch/Hes1 信号发挥肿瘤抑制作用。用化合物 12 处理 HCT-116 细胞会导致 Hes1 下调和抗肿瘤作用。
