Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity

  • J Med Chem. 2014 May 22;57(10):4289-301. doi: 10.1021/jm5002452.
Sujeewa Ranatunga  1 ,  Chih-Hang Anthony Tang ,  Chang Won Kang ,  Crystina L Kriss ,  Bernhard J Kloppenburg ,  Chih-Chi Andrew Hu ,  Juan R Del Valle
Affiliations
  • 1. Drug Discovery Department and ‡Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive MRC3E, Tampa, Florida 33612, United States.
PMID: 24749861 DOI: 10.1021/jm5002452
Abstract

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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