Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity
S Ranatunga, CHA Tang, CW Kang… - Journal of medicinal …, 2014 - ACS Publications
Journal of medicinal chemistry, 2014•ACS Publications
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 …
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 …
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.
ACS Publications