6 research outputs found
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Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein–Protein Interaction
The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro characterization of a series of rigidified mimetic of this prototypic inhibitor in which the phenyl in the 2-(4-(3,4-dichlorophenyl)thiazol-2-yl) moiety was bridged into a tricyclic system. The bridge consisted one of the following: ethylene, methylene oxide, methylenesulfide, methylenesulfoxide, and methylenesulfone. Numerous analogues in this series were found to be markedly more potent than the parent prototypic inhibitor in the inhibition of eIF4E/eIF4G interaction, thus preventing the eIF4F complex formation, a rate limiting step in the translation initiation cascade in eukaryotes, and in inhibition of human cancer cell proliferation
Structureeactivity relationship study of 4EGI-1, small molecule eIF4E/eIF4G proteineprotein interaction inhibitors
International audienceProteineprotein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2- nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G proteineprotein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities
Explorations of Substituted Urea Functionality for the Discovery of New Activators of the Heme-Regulated Inhibitor Kinase
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
Explorations of Substituted Urea Functionality for the Discovery of New Activators of the Heme-Regulated Inhibitor Kinase
Heme-regulated inhibitor kinase (HRI), an 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 biology of this important kinase. To expand the repertoire of chemotypes that activate HRI we screened a ~1,900 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 contributions of substitutions on the N-aryl and N′-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogs. 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