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Discovery of a ZIP7 inhibitor from a Notch pathway screen

Nolin, Erin and Gans, Sara and Llamas, Luis and Bandyopadhyay, Somnath and Brittain, Scott M. and Bernasconi-Elias, Paula and Carter, Kyle P. and Loureiro, Joseph J. and Thomas, Jason R. and Schirle, Markus and Yang, Yi and Guo, Ning and Roma, Guglielmo and Schuierer, Sven and Beibel, Martin and Lindeman, Alicia and Sigoillot, Frederic and Chen, Amy and Xie, Kevin X. and Ho, Samuel and Reece-Hoyes, John and Weihofen, Wilhelm A. and Tyskiewicz, Kayla and Hoepfner, Dominic and McDonald, Richard I. and Guthrie, Nicolette and Dogra, Abhishek and Guo, Haibing and Shao, Jian and Ding, Jian and Canham, Stephen M. and Boynton, Geoff and George, Elizabeth L. and Kang, Zhao B. and Antczak, Christophe and Porter, Jeffery A. and Wallace, Owen and Tallarico, John A. and Palmer, Amy E. and Jenkins, Jeremy L. and Jain, Rishi K. and Bushell, Simon M. and Fryer, Christy J. (2019) Discovery of a ZIP7 inhibitor from a Notch pathway screen. Nature Chemical Biology. ISSN 1552-4450

Abstract

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.

Item Type: Article
Date Deposited: 26 Jan 2019 00:45
Last Modified: 26 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/38784

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