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Chembiochem. 2013 Jul 8;14(10):1255-62. doi: 10.1002/cbic.201300177. Epub 2013 Jun 19.

Dual activators of protein kinase R (PKR) and protein kinase R-like kinase PERK identify common and divergent catalytic targets.

Bai H#1,2,3, Chen T#2,3, Ming J3, Sun H3,4, Cao P3, Fusco DN5, Chung RT5, Chorev M2,3, Jin Q1, Aktas BH2,3.

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Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, 6 Rong Jing Jie, Beijing 100176, China.
Hematology Laboratory for Translational Research, Department of Medicine. Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Harvard Medical School, 240 Longwood Avenue, Boston MA 02115.
Basic Medical College, Hebei United University, Tangshan, Hebei, 063000, China.
Gastrointestinal Unit, Massachusetts General Hospital Boston MA 02114.
Contributed equally


Chemical genetics has evolved into a powerful tool for studying gene function in normal and pathobiology. PKR and PERK, two eukaryotic translation initiation factor 2 alpha (eIF2α) kinases, play critical roles in the maintenance of cellular hemostasis, metabolic stability, and anti-viral defenses. Both kinases interact with and phosphorylate additional substrates including tumor suppressor p53 and nuclear protein 90. Loss of function of both kinases has been studied by reverse genetics and with recently identified inhibitors. In contrast, no activating probes for studying the catalytic activity of these kinases are available. We identified 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dihydroxy-4H-chromen-4-one (DHBDC) as a specific dual activator of PKR and PERK by screening a chemical library of 20 000 small molecules in a dual luciferase surrogate eIF2α phosphorylation assay. We present here extensive biological characterization and a preliminary structure-activity relationship of DHBDC, which phosphorylates eIF2α by activating PKR and PERK but no other eIF2α kinases. These agents also activate downstream effectors of eIF2α phosphorylation by inducing CEBP homologue protein, suppressing cyclin D1 expression, and inhibiting cancer cell proliferation, all in a manner dependent on PKR and PERK. Consistent with the role of eIF2α phosphorylation in viral infection, DHBDC inhibits the proliferation of human hepatitis C virus. Finally, DHBDC induces the phosphorylation of IκBα and activates the NF-κB pathway. Surprisingly, activation of the NF-κB pathway is dependent on PERK but independent of PKR activity. These data indicate that DHBDC is an invaluable probe for elucidating the role of PKR and PERK in normal and pathobiology.


NF-κB; chemical genetics; eIF2α; endoplasmic reticulum stress; kinases

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