Explorations of Substituted Urea Functionality for the Discovery of New Activators of the Heme-Regulated Inhibitor Kinase

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9457-9470
• 全文大小：630K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2伪) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as 尾-thalassemia. We previously identified N,N鈥?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鈥?disubstituted urea library in the surrogate eIF2伪 phosphorylation assay, identifying N-aryl,N鈥?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鈥?cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N鈥?cyclohexylphenoxyureas in the surrogate eIF2伪 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.