NVS-ZP7-4 was identified as a novel chemical reagent targeting the zinc input protein ZIP7, which accounts for the zinc surge from the apparatus to the cytoplasm. Since zinc dysregulation is related to multiple diseases, in this study, we aimed to identify the anti-tumor effects of NVS-ZP7-4 and explore the molecular mechanisms of NVS-ZP7-4 in hepatocellular carcinoma (HCC) progression. We found that NVS-ZP7-4 inhibited cell viability, caused cell cycle arrest, induced apoptosis, and inhibited the proliferation, migration, and invasion of HCCLM3 and Huh7 cells. We further investigated the inhibited activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was involved in the antitumor effect of NVS-ZP7-4 in HCC. Furthermore, NVS-ZP7-4 inhibited HCC tumor growth in vivo. The present study demonstrated that NVS-ZP7-4 is a promising therapeutic target for HCC by regulating PI3K/AKT signaling.

01 Feb 2019·Nature Chemical Biology

Discovery of a ZIP7 inhibitor from a Notch pathway screen

Article

Author: Dogra, Abhishek ; Antczak, Christophe ; Bushell, Simon M ; Brittain, Scott M ; Carter, Kyle P ; Thomas, Jason R ; Roma, Guglielmo ; Schuierer, Sven ; George, Elizabeth L ; Sigoillot, Frederic ; Xie, Kevin X ; Wallace, Owen ; Boynton, Geoff ; Schirle, Markus ; Guthrie, Nicolette ; Tallarico, John A ; Weihofen, Wilhelm A ; Jain, Rishi K ; Yang, Yi ; Chen, Amy ; Guo, Haibing ; Bernasconi-Elias, Paula ; Reece-Hoyes, John ; Kang, Zhao B ; Guo, Ning ; Ho, Samuel ; Shao, Jian ; Loureiro, Joseph J ; Lindeman, Alicia ; Palmer, Amy E ; McDonald, Richard I ; Ding, Jian ; Beibel, Martin ; Jenkins, Jeremy L ; Canham, Stephen M ; Tyskiewicz, Kayla ; Hoepfner, Dominic ; Nolin, Erin ; Porter, Jeffery A ; Gans, Sara ; Bandyopadhyay, Somnath ; Llamas, Luis ; Fryer, Christy J

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.

Journal of Agricultural and Food Chemistry

Structural Characterization of Zinc-Sucrose Complex and Its Ability to Promote Zinc Absorption in Caco-2 Monolayer Cells and Mice

Author: Deng, Zeyuan ; Wang, Ruiyan ; Du, Qian ; Zhou, Jianqun ; Zheng, Liufeng ; Li, Wenwen ; Li, Nan

Sucrose emerges as a metal-ion chelating agent with excellent stability that may increase metal-ion absorption.This study aimed to characterize the structure of zinc-sucrose complex and investigate its ability to promote zinc absorption in Caco-2 monolayer cells and mice.Based on the results of the inductively coupled plasma emission spectrometer (ICP-ES), SEM-energy-dispersive X-ray spectroscopy (SEM-EDX), and Fourier transform IR spectroscopy (FT-IR), it can be inferred that zinc and sucrose were chelated at a 1:1 ratio, with the hydroxyl groups playing a significant role.The Caco-2 monolayer cell model revealed that zinc-sucrose complex increased the amount of zinc uptake, retention, and transport in a dose- and time-dependent manner.Through the upregulation of genes and proteins for ZIP4, MT1, and DMT1, treatment with zinc-sucrose complex improved the proportion of absorbed zinc utilized for transport compared to ZnCl2 (26.21 ± 4.96 vs. 8.50 ± 1.51%).Pharmacokinetic anal. of mice confirmed the zinc absorption-promoting effect of zinc-sucrose complex, as indicated by the considerably higher serum zinc level (4.16 ± 0.53 vs. 2.56 ± 0.45 mg/L) and intestinal ZIP4, MT1, and DMT1 gene expression than ZnCl2.Further treatment of different zinc channel inhibitors and CETSA demonstrated the direct interaction of zinc-sucrose complex with ZIP4 protein and ZIP4-mediated cellular transport of zinc-sucrose complex.These findings provide a novel insight into the zinc absorption-promoting mechanism of zinc-sucrose complex, which could be used as an ingredient in functional foods to treat zinc deficiency.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Preclinical	Switzerland	Novartis AG	14 Jan 2019

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