从 Notch 通路筛选中发现 ZIP7 抑制剂。
Discovery of a ZIP7 inhibitor from a Notch pathway screen.
机构信息
Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
出版信息
Nat Chem Biol. 2019 Feb;15(2):179-188. doi: 10.1038/s41589-018-0200-7. Epub 2019 Jan 14.
The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.
在 50%的 T 细胞急性淋巴细胞白血病中鉴定出 NOTCH1 的激活突变，这引起了人们的兴趣，即研究这些突变如何促进致癌转化，并针对该途径进行靶向治疗。表型筛选鉴定出了一些化合物，这些化合物通过内质网 (ER) 应激机制干扰 Notch 的运输并诱导细胞凋亡。靶标鉴定方法表明，SLC39A7（ZIP7）在调节 Notch 运输和信号转导中发挥作用，SLC39A7 是一种锌转运家族成员。生成并测序一个化合物抗性细胞系，鉴定出 ZIP7 中的 V430E 突变，该突变赋予对化合物 NVS-ZP7-4 的可传递抗性。NVS-ZP7-4 改变了 ER 中的锌，并且该化合物的类似物通过光亲和标记在细胞中标记 ZIP7，这表明化合物与 ZIP7 之间存在直接相互作用。NVS-ZP7-4 是第一个报道的用于研究调节 ER 锌水平的影响以及将 ZIP7 作为 Notch 途径中的新型可成药节点的化学工具。
Zotero 插件