Discovery of a ZIP7 inhibitor from a Notch pathway screen

  • Nat Chem Biol. 2019 Feb;15(2):179-188. doi: 10.1038/s41589-018-0200-7.
Erin Nolin  1 ,  Sara Gans  1 ,  Luis Llamas  1 ,  Somnath Bandyopadhyay  1 ,  Scott M Brittain  1 ,  Paula Bernasconi-Elias  1 ,  Kyle P Carter  2 ,  Joseph J Loureiro  1 ,  Jason R Thomas  1 ,  Markus Schirle  1 ,  Yi Yang  1 ,  Ning Guo  1 ,  Guglielmo Roma  3 ,  Sven Schuierer  3 ,  Martin Beibel  3 ,  Alicia Lindeman  1 ,  Frederic Sigoillot  1 ,  Amy Chen  1 ,  Kevin X Xie  1 ,  Samuel Ho  1 ,  John Reece-Hoyes  1 ,  Wilhelm A Weihofen  1 ,  Kayla Tyskiewicz  1 ,  Dominic Hoepfner  3 ,  Richard I McDonald  1 ,  Nicolette Guthrie  1 ,  Abhishek Dogra  1 ,  Haibing Guo  4 ,  Jian Shao  1 ,  Jian Ding  1 ,  Stephen M Canham  1 ,  Geoff Boynton  1 ,  Elizabeth L George  1 ,  Zhao B Kang  1 ,  Christophe Antczak  1 ,  Jeffery A Porter  1 ,  Owen Wallace  1 ,  John A Tallarico  1 ,  Amy E Palmer  2 ,  Jeremy L Jenkins  1 ,  Rishi K Jain  1 ,  Simon M Bushell  5 ,  Christy J Fryer  6
Affiliations
  • 1. Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 2. Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
  • 3. Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • 4. Novartis Institutes for Biomedical Research, Shanghai, China.
  • 5. Novartis Institutes for Biomedical Research, Cambridge, MA, USA. [email protected].
  • 6. Novartis Institutes for Biomedical Research, Cambridge, MA, USA. [email protected].
PMID: 30643281 DOI: 10.1038/s41589-018-0200-7
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.

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