Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response

作者：Yefidoff-Freedman, Revital; Fan, Jing; Yan, Lu; Zhang, Qingwen; dos Santos, Guillermo Rodrigo Reis; Rana, Sandeep; Contreras, Jacob I.; Sahoo, Rupam; Wan, Debin; Young, Jun; Teixeira, Karina Luiza Dias; Morisseau, Christophe; Halperin, Jose; Hammock, Bruce; Natarajan, Amarnath; Wang, Peimin; Chorev, Michael; Aktas, Bertal H.^*

来源：Journal of Medicinal Chemistry, 2017, 60(13): 5392-5406.

DOI：10.1021/acs.jmedchem.7b00059

• GUANINE-NUCLEOTIDE EXCHANGE
• PROTEIN-KINASE-R
• TRANSLATION INITIATION
• IN-VITRO
• EXPRESSION
• SORAFENIB
• DEPLETION
• POTENT
• LINKS

Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2 alpha, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycydohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2 alpha phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies, we undertook bioassay-guided structure-activity relationship studies and tested them in the surrogate eIF2 alpha phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2 alpha phosphorylation and in the expression of the transcription factor C/EBP homologous protein (CHOP) and its mRNA, demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.

• 出版日期2017-7-13
• 单位上海医药工业研究院; 南京中医药大学; 江苏省中医院