2. Academic Validation
  3. Structure-Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response

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

  • ChemMedChem. 2016 Apr 19;11(8):870-80. doi: 10.1002/cmdc.201500483.
Brian R Hearn 1,  Priyadarshini Jaishankar 1,  Carmela Sidrauski 2,  Jordan C Tsai 2,  Punitha Vedantham 1,  Shaun D Fontaine 1,  Peter Walter 3,  Adam R Renslo 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry and, Small Molecule Discovery Center, University of California, San Francisco, CA, 94158, USA.
  • 2 Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA, 94158, USA.
  • 3 Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA, 94158, USA. peter@walterlab.ucsf.edu.
  • 4 Department of Pharmaceutical Chemistry and, Small Molecule Discovery Center, University of California, San Francisco, CA, 94158, USA. adam.renslo@ucsf.edu.
PMID: 26789650 DOI: 10.1002/cmdc.201500483
Abstract

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.

Keywords

ISRIB; integrated stress response; protein-protein interactions; structure-activity relationships; unfolded protein response.

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