Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch
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 amid...
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eLife Sciences Publications Ltd
2016-07-01
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| Online Access: | https://elifesciences.org/articles/11878 |
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doaj-44b158715f4e4880ab40be484472e49b2021-05-05T00:29:43ZengeLife Sciences Publications LtdeLife2050-084X2016-07-01510.7554/eLife.11878Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branchCiara M Gallagher0Carolina Garri1Erica L Cain2Kenny Kean-Hooi Ang3Christopher G Wilson4Steven Chen5Brian R Hearn6Priyadarshini Jaishankar7Andres Aranda-Diaz8Michelle R Arkin9Adam R Renslo10Peter Walter11https://orcid.org/0000-0002-6849-708XDepartment of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United StatesDepartment of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States; Fundación Ciencia Para la Vida, Santiago, ChileDepartment of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United StatesThe 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.https://elifesciences.org/articles/11878endoplasmic reticulumunfolded protein responsesmall molecule screeningATF6-alphasite-1-proteaseER to Golgi trafficking |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch eLife endoplasmic reticulum unfolded protein response small molecule screening ATF6-alpha site-1-protease ER to Golgi trafficking |
| author_facet |
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 |
| author_sort |
Ciara M Gallagher |
| title |
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch |
| title_short |
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch |
| title_full |
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch |
| title_fullStr |
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch |
| title_full_unstemmed |
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch |
| title_sort |
ceapins are a new class of unfolded protein response inhibitors, selectively targeting the atf6α branch |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2016-07-01 |
| description |
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. |
| topic |
endoplasmic reticulum unfolded protein response small molecule screening ATF6-alpha site-1-protease ER to Golgi trafficking |
| url |
https://elifesciences.org/articles/11878 |
| work_keys_str_mv |
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