Structure-Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response

Brian R HearnAdam R Renslo


The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular stress that converge at a single event-the phosphorylation of Ser51 on the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α-P) results in attenuation of global protein synthesis via the inhibitory effects of eIF2α-P on eIF2B, the guanine exchange factor (GEF) for eIF2. Herein we describe structure-activity relationship (SAR) studies of bis-O-arylglycolamides, first-in-class integrated stress response inhibitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α-P by activating the GEF activity of eIF2B and allowing global protein synthesis to proceed with residual unphosphorylated eIF2α. The SAR studies described herein support the proposed pharmacology of ISRIB analogues as binding across a symmetrical protein-protein interface formed between protein subunits of the dimeric eIF2B heteropentamer.


Jun 15, 2007·Nature Reviews. Molecular Cell Biology·D Ron, Peter Walter
Dec 14, 2007·Nature·James A Wells, Christopher L McClendon
Jan 25, 2012·Nature Chemistry·G Richard BickertonAndrew L Hopkins
Oct 13, 2012·Annual Review of Cell and Developmental Biology·Alexei Korennykh, Peter Walter
Jan 29, 2013·Cellular and Molecular Life Sciences : CMLS·Neysan DonnellyAfshin Samali
Aug 31, 2013·Nature Reviews. Drug Discovery·Claudio HetzHeather P Harding
Feb 18, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Noel C WorthamChristopher G Proud
May 24, 2014·Nature Communications·Yuliya GordiyenkoCarol V Robinson
Sep 23, 2014·Chemistry & Biology·Michelle R ArkinJames A Wells
Jan 6, 2015·Neuropathology and Applied Neurobiology·M Halliday, G R Mallucci


Feb 15, 2018·Cold Spring Harbor Perspectives in Biology·Jennifer Chu, Jerry Pelletier
Feb 17, 2017·Biochemical Society Transactions·Jeyapriya R SundaramShirish Shenolikar
Feb 18, 2020·Nature·Xiaheng ZhangDavid W C MacMillan
Jul 20, 2019·Nature Chemical Biology·Claudio HetzJohn B Patterson
Aug 14, 2019·Annals of Clinical and Translational Neurology·Truus E M AbbinkMarjo S van der Knaap
Jan 22, 2021·Current Eye Research·Hsiao-Sang ChuJames Foster

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