1. Academic Validation
  2. Small molecules intercept Notch signaling and the early secretory pathway

Small molecules intercept Notch signaling and the early secretory pathway

  • Nat Chem Biol. 2013 Nov;9(11):731-8. doi: 10.1038/nchembio.1356.
Andreas Krämer 1 Torben Mentrup Bertrand Kleizen Eric Rivera-Milla Daniela Reichenbach Christoph Enzensperger Richard Nohl Eric Täuscher Helmar Görls Aspasia Ploubidou Christoph Englert Oliver Werz Hans-Dieter Arndt Christoph Kaether
Affiliations

Affiliation

  • 1 Leibniz Institut für Altersforschung-Fritz Lipmann Institut, Jena, Germany.
Abstract

Notch signaling has a pivotal role in numerous cell-fate decisions, and its aberrant activity leads to developmental disorders and Cancer. To identify molecules that influence Notch signaling, we screened nearly 17,000 compounds using automated microscopy to monitor the trafficking and processing of a ligand-independent Notch-enhanced GFP (eGFP) reporter. Characterization of hits in vitro by biochemical and cellular assays and in vivo using zebrafish led to five validated compounds, four of which induced accumulation of the reporter at the plasma membrane by inhibiting γ-secretase. One compound, the dihydropyridine FLI-06, disrupted the Golgi apparatus in a manner distinct from that of brefeldin A and golgicide A. FLI-06 inhibited general secretion at a step before exit from the endoplasmic reticulum (ER), which was accompanied by a tubule-to-sheet morphological transition of the ER, rendering FLI-06 the first small molecule acting at such an early stage in secretory traffic. These data highlight the power of phenotypic screening to enable investigations of central cellular signaling pathways.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15860
    99.90%, Notch抑制剂