1 research outputs found
Synthesis of Novel Tricyclic Chromenone-Based Inhibitors of IRE‑1 RNase Activity
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-<i>c</i>]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 <b>30</b> 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