Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase

Ting Chen, Khuloud Takrouri, Sung Hee-Hwang, Sandeep Rana, Revital Yefidoff-Freedman, Jose Halperin, Amarnath Natarajan, Christophe Morisseau, Bruce Hammock, Michael Chorev, Bertal H. Aktas

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as β-thalassemia. We previously identified N,N′-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ∼1900 member N,N′-disubstituted urea library in the surrogate eIF2α phosphorylation assay, identifying N-aryl,N′-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N′-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N′- cyclohexylphenoxyureas in the surrogate eIF2α phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.

Original languageEnglish (US)
Pages (from-to)9457-9470
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number23
DOIs
StatePublished - Dec 12 2013

Fingerprint

Heme
Urea
Phosphotransferases
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Phosphorylation
Cell Proliferation
Thalassemia
Libraries
Cell Differentiation
Hemoglobins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Chen, T., Takrouri, K., Hee-Hwang, S., Rana, S., Yefidoff-Freedman, R., Halperin, J., ... Aktas, B. H. (2013). Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. Journal of Medicinal Chemistry, 56(23), 9457-9470. https://doi.org/10.1021/jm400793v

Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. / Chen, Ting; Takrouri, Khuloud; Hee-Hwang, Sung; Rana, Sandeep; Yefidoff-Freedman, Revital; Halperin, Jose; Natarajan, Amarnath; Morisseau, Christophe; Hammock, Bruce; Chorev, Michael; Aktas, Bertal H.

In: Journal of Medicinal Chemistry, Vol. 56, No. 23, 12.12.2013, p. 9457-9470.

Research output: Contribution to journalArticle

Chen, T, Takrouri, K, Hee-Hwang, S, Rana, S, Yefidoff-Freedman, R, Halperin, J, Natarajan, A, Morisseau, C, Hammock, B, Chorev, M & Aktas, BH 2013, 'Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase', Journal of Medicinal Chemistry, vol. 56, no. 23, pp. 9457-9470. https://doi.org/10.1021/jm400793v
Chen, Ting ; Takrouri, Khuloud ; Hee-Hwang, Sung ; Rana, Sandeep ; Yefidoff-Freedman, Revital ; Halperin, Jose ; Natarajan, Amarnath ; Morisseau, Christophe ; Hammock, Bruce ; Chorev, Michael ; Aktas, Bertal H. / Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 23. pp. 9457-9470.
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