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

• DOI: 10.7554/elife.11878
• Publication Date: 2016-07-18T13:59:32Z
• Authors: Ciara M Gallagher; Carolina Garri; Erica L Cain; Kenny Kean-Hooi Ang; Christopher G Wilson; Steven Chen; Brian R Hearn; Priyadarshini Jai...; Andres Aranda-Diaz; Michelle R Arkin; Adam R Renslo; Peter Walter
• Keywords: 0301 basic medicine; QH301-705.5; Cell Survival; Science; Drug Evaluation, Preclinical; Cell Line; 03 medical and health sciences; Humans; Biology (General); Enzyme Inhibitors; Q; R; unfolded protein response; Cell Biology; small molecule screening; Activating Transcription Factor 6; High-Throughput Screening Assays; 3. Good health; endoplasmic reticulum; ATF6-alpha; ER to Golgi trafficking; site-1-protease; Unfolded Protein Response; Medicine; Pyrazoles

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.