2. Academic Validation
  3. Discovery of a ZIP7 inhibitor from a Notch pathway screen

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

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. simon.bushell@novartis.com.
  • 6 Novartis Institutes for Biomedical Research, Cambridge, MA, USA. christy.fryer@novartis.com.
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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