Discovery of a ZIP7 inhibitor from a Notch pathway screen.

Discovery of a ZIP7 inhibitor from a Notch pathway screen.

Nature chemical biology (2019-01-16)

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

PMID30643281

摘要

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.