title: Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.
authors.forename: Ciara M
authors.initials: CM
authors.lastname: Gallagher
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.|Fundación Ciencia Para la Vida, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Garri
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Cain
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Kenny Kean-Hooi
authors.initials: KK
authors.lastname: Ang
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wilson
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hearn
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Jaishankar
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.
authors.forename: Andres
authors.initials: A
authors.lastname: Aranda-Diaz
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.
authors.forename: Peter
authors.identifier: 0000-0002-6849-708X
authors.initials: P
authors.lastname: Walter
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D011720:Pyrazoles / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004791:Enzyme Inhibitors; D011720:Pyrazoles
keywords: ATF6-alpha; ER to Golgi trafficking; cell biology; endoplasmic reticulum; human; site-1-protease; small molecule screening; unfolded protein response