Design and synthesis of novel protein kinase R (PKR) inhibitors

By: Weintraub S., Yarnitzky T., Kahremany S., Barrera I., Viskind O., Rosenblum K., Niv M.Y., Gruzman A.
Published in: Molecular Diversity
SDGs : SDG 03  |  Units: Natural Sciences  | Time: 2016 |  Link
Description: Protein kinase RNA-activated (PKR) plays an important role in a broad range of intracellular regulatory mechanisms and i n the pathophysiology of many human diseases, including microbial and viral infections, cancer, diabetes and neurodegenerative disorders. Recently, several potent PKR inhibitors have been synthesized. However, the enzyme’s multifunctional character and a multitude of PKR downstream targets have prevented the successful transformation of such inhibitors into effective drugs. Thus, the need for additional PKR inhibitors remains. With the help of computer-aided drug-discovery tools, we designed and synthesized potential PKR inhibitors. Indeed, two compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One compound, 6-amino-3-methyl-2-oxo-N-phenyl-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide, also showed anti-apoptotic properties. The novel molecules diversify the existing pool of PKR inhibitors and provide a basis for the future development of compounds based on PKR signal transduction mechanism. © 2016, Springer International Publishing Switzerland.