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Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

Ciara M Gallagher1, Carolina Garri1,2, Erica L Cain1

  • 1Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.

Elife
|July 21, 2016
PubMed

Insights

Researchers developed Ceapins, novel pyrazole amides, to block ATF6α signaling during ER stress. These inhibitors selectively target the unfolded protein response, offering new ways to study and treat diseases involving ER stress.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Pharmacology

Background:

  • The transcription factor ATF6α is crucial for cell survival under ER stress as part of the unfolded protein response (UPR).
  • ATF6α activation supports cell survival in various cancer models.
  • Targeting ATF6α offers a potential therapeutic strategy for diseases involving ER stress.

Purpose of the Study:

  • To discover and develop novel inhibitors of ATF6α signaling.
  • To create pharmacological tools for investigating the UPR and ATF6α function.
  • To enable selective modulation of UPR pathways.

Main Methods:

  • Utilized cell-based screening to identify and characterize Ceapins, a class of pyrazole amides.
  • Assessed the specificity of Ceapins against ATF6α signaling and other UPR branches.
  • Evaluated the impact of Ceapins on cells under ER stress and normal conditions.

Main Results:

  • Discovered Ceapins as specific inhibitors of ATF6α signaling.
  • Demonstrated that Ceapins sensitize cells to ER stress without affecting unstressed cell viability.
  • Confirmed Ceapins do not interfere with other UPR pathways, ATF6β processing, or SREBP activity.

Conclusions:

  • Ceapins are the first-in-class inhibitors targeting ATF6α signaling.
  • These compounds provide valuable tools for mechanistic studies of ATF6α activation and its role in pathology.
  • The development of Ceapins allows for the pharmacological manipulation of all three UPR branches, individually or in combination.
Keywords:
ATF6-alphaER to Golgi traffickingcell biologyendoplasmic reticulumhumansite-1-proteasesmall molecule screeningunfolded protein response

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