Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch
Ciara M Gallagher,
Carolina Garri,
Erica L Cain,
Kenny Kean-Hooi Ang,
Christopher G Wilson,
Steven Chen,
Brian R Hearn,
Priyadarshini Jaishankar,
Andres Aranda-Diaz,
Michelle R Arkin,
Adam R Renslo,
Peter Walter
Affiliations
Ciara M Gallagher
Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
Carolina Garri
Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States; Fundación Ciencia Para la Vida, Santiago, Chile
Erica L Cain
Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
Kenny Kean-Hooi Ang
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Christopher G Wilson
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Steven Chen
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Brian R Hearn
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Priyadarshini Jaishankar
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Andres Aranda-Diaz
Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
Michelle R Arkin
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Adam R Renslo
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.
