Explorations of Substituted
Urea Functionality for
the Discovery of New Activators of the Heme-Regulated Inhibitor Kinase
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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 <i>N</i>,<i>N</i>′-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 <i>N</i>,<i>N</i>′-disubstituted
urea library in the surrogate eIF2α phosphorylation assay, identifying <i>N</i>-aryl,<i>N</i>′-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 <i>N</i>-aryl and <i>N</i>′-cyclohexylphenoxy groups to their activity by studying focused
libraries of complementing analogues. We tested these <i>N</i>-aryl,<i>N</i>′-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