title: Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase.
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.
authors.affiliation: Hematology Laboratory for Translational Research, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , 75 Francis Street, Boston, Massachusetts 02115, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Khuloud
authors.initials: K
authors.lastname: Takrouri
authors.forename: Sung
authors.initials: S
authors.lastname: Hee-Hwang
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rana
authors.forename: Revital
authors.initials: R
authors.lastname: Yefidoff-Freedman
authors.forename: Jose
authors.initials: J
authors.lastname: Halperin
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bruce
authors.initials: B
authors.lastname: Hammock
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D014508:Urea; D019892:eIF-2 Kinase