Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 10, Pages 4289-4301Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5002452
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Funding
- National Institutes of Health [R01CA163910]
- American Cancer Society [IRG9309214, IRG9303216]
- Moffitt Team Science award
- Miles for Moffitt Foundation
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Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.
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