Small molecule modulators of eukaryotic initiation factor 2α kinases, the key regulators of protein synthesis.
Eukaryotic initiation factor 2 alpha kinases (eIF-2α kinases) are key mediators of stress response in cells. In mammalian cells, there are four eIF-2α kinases, namely HRI (Heme-Regulated Inhibitor), PKR (RNA-dependent Protein Kinase), PERK (PKR-like ER Kinase) and GCN2 (General Control Non-derepressible 2). These kinases get activated during diverse cytoplasmic stress conditions and phosphorylate the alpha-subunit of eIF2, leading to global protein synthesis inhibition. Therefore, eIF-2α kinases play a vital role in various cellular processes such as proliferation, differentiation, apoptosis and cell signaling. Deregulation of eIF-2α kinases and protein synthesis has been linked to numerous pathological conditions such as certain cancers, anemia and neurodegenerative disorders. Thus, modulation of these kinases by small molecules holds a great therapeutic promise. In this review we have compiled the available information on inhibitors and activators of these four eIF-2α kinases. The review concludes with a note on the selectivity issue of currently available modulators and future perspectives for the design of specific small molecule probes.
Bioinformatics Center, University of Pune, Pune - 411007, Maharashtra, India. Electronic address: manali@bioinfo.net.in.
Manali
M
Joshi
Abhijeet
A
Kulkarni
Jayanta K
JK
Pal
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D004791:Enzyme Inhibitors; C460640:EIF2AK3 protein, human; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase
Activator; GCN2; HRI; Inhibitor; PERK; PKR; eIF-2α kinases