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Discovery of a ZIP7 inhibitor from a Notch pathway screen

Erin Nolin1, Sara Gans1, Luis Llamas1

  • 1Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

Nature Chemical Biology
|January 16, 2019
PubMed

Insights

Activating NOTCH1 mutations drive T cell acute lymphoblastic leukemia. Researchers found compounds targeting endoplasmic reticulum (ER) zinc levels via SLC39A7 (ZIP7) induce cancer cell death, offering a new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • Activating mutations in NOTCH1 are prevalent in T cell acute lymphoblastic leukemia (T-ALL), highlighting the pathway's oncogenic role.
  • Targeting the NOTCH pathway is a promising therapeutic strategy for T-ALL, but requires understanding its molecular underpinnings.

Purpose of the Study:

  • To identify novel therapeutic targets and chemical tools for T-ALL by investigating the NOTCH pathway.
  • To elucidate the mechanism by which compounds targeting Notch signaling induce apoptosis in T-ALL cells.

Main Methods:

  • Phenotypic screening identified compounds inducing apoptosis via endoplasmic reticulum (ER) stress.
  • Target identification revealed SLC39A7 (ZIP7) as a regulator of Notch trafficking and signaling.
  • Compound-resistant cell lines and photoaffinity labeling were used to confirm direct interaction between NVS-ZP7-4 and ZIP7.

Main Results:

  • Compounds were identified that disrupt Notch trafficking and induce apoptosis through ER stress.
  • SLC39A7 (ZIP7) was identified as a key mediator of Notch signaling.
  • The compound NVS-ZP7-4 directly interacts with ZIP7, modulates ER zinc levels, and induces cancer cell death.

Conclusions:

  • NVS-ZP7-4 is a novel chemical probe that modulates ER zinc levels and targets ZIP7.
  • ZIP7 represents a druggable node within the NOTCH pathway, offering a new therapeutic avenue for T-ALL.
  • Modulating ER zinc homeostasis is a potential strategy for cancer therapy.

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