Nolin, Erin, Gans, Sara, Llamas, Luis, Brittain, Scott, Loureiro, Joe, Thomas, Jason, Schirle, Markus, Yang, Yi, Guo, Ning, Roma, Guglielmo, Schuierer, Sven, Beibel, Martin, Lindeman, Alicia, Sigoillot, Frederic, Chen, Amy, Xie, Kevin, Ho, Samuel, Hoepfner, Dominic, Mcdonald, Rick, Dogra, Abhishek, Ding, Jian, Canham, Steve, Boynton, Geoffrey, George, Elizabeth, Kang, Zhao Bin, Antczak, Christophe, Porter, Jeffrey, Tallarico, John, Jenkins, Jeremy, Jain, Rishi, Bushell, Simon, Fryer, Christy, Reece-Hoyes, John, Tyskiewicz, Kayla and Weihofen, Wilhelm (2019) Discovery of a ZIP7 Inhibitor from a Notch Pathway Screen. Nature chemical biology, 15. pp. 179-188. ISSN 1552-4469

Abstract

The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the Notch signaling pathway in this disease. The receptors and ligands of the Notch signaling pathway must be trafficked to the cell surface where they interact and activate signaling. A phenotypic screen for inhibitors of the Notch signaling pathway identified compounds that interfere with trafficking of Notch to the cell surface, and induce apoptosis in T-ALL via an ER stress mechanism. Comprehensive target identification approaches revealed a role for SLC39A7 / ZIP7, a Zrt-, Irt-like protein 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, but not the cytosol, suggesting ER zinc homeostasis is critical to both Notch signaling and ER stress. A diazirine-containing analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. The ZIP and the Zn transporter (ZnT) family of zinc transporters are found in all aspects of life, and both families of transporters play critical roles in cellular and physiological functions. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and to further investigate ZIP7 as a novel druggable node in the Notch pathway.

Item Type:	Article
Date Deposited:	19 Feb 2019 00:45
Last Modified:	19 Feb 2019 00:45
URI:	https://oak.novartis.com/id/eprint/36953