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

Sagiv Weintraub, Tali Yarnitzky, Shirin Kahremany, Iliana Barrera, Olga Viskind, Kobi Rosenblum, Masha Y. Niv, Arie Gruzman

Research output: Contribution to journalArticlepeer-review

Abstract

Protein kinase RNA-activated (PKR) plays an important role in a broad range of intracellular regulatory mechanisms and in 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.

Original languageEnglish
Pages (from-to)805-819
Number of pages15
JournalMolecular Diversity
Volume20
Issue number4
DOIs
StatePublished - 1 Nov 2016

Bibliographical note

Funding Information:
This study was partly supported by a Bar-Ilan-University new faculty Grant for A.G. This study was also supported by a KAMIN program grant (Israel Ministry of Industry, Trade and Labour) for M.Y.N. and K.R. We would like to thank Nechama-Sara Cohen for the English editing of the manuscript.

Publisher Copyright:
© 2016, Springer International Publishing Switzerland.

Keywords

  • Benzoimidazole derivatives
  • C16
  • Computer modelling
  • PKR inhibitors

ASJC Scopus subject areas

  • Catalysis
  • Information Systems
  • Molecular Biology
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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