TY - JOUR
T1 - Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase
AU - Chen, Ting
AU - Takrouri, Khuloud
AU - Hee-Hwang, Sung
AU - Rana, Sandeep
AU - Yefidoff-Freedman, Revital
AU - Halperin, Jose
AU - Natarajan, Amarnath
AU - Morisseau, Christophe
AU - Hammock, Bruce
AU - Chorev, Michael
AU - Aktas, Bertal H.
PY - 2013/12/12
Y1 - 2013/12/12
N2 - 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.
AB - 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.
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U2 - 10.1021/jm400793v
DO - 10.1021/jm400793v
M3 - Article
C2 - 24261904
AN - SCOPUS:84890449347
VL - 56
SP - 9457
EP - 9470
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -