2. Academic Validation
  3. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors

Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors

  • Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202.
Mario Sanches 1,  Nicole M Duffy 1,  Manisha Talukdar 2,  Nero Thevakumaran 3,  David Chiovitti 4,  Marella D Canny 4,  Kenneth Lee 5,  Igor Kurinov 6,  David Uehling 7,  Rima Al-awar 8,  Gennadiy Poda 7,  Michael Prakesch 7,  Brian Wilson 7,  Victor Tam 9,  Colleen Schweitzer 9,  Andras Toro 9,  Julie L Lucas 9,  Danka Vuga 9,  Lynn Lehmann 10,  Daniel Durocher 5,  Qingping Zeng 9,  John B Patterson 9,  Frank Sicheri 11
Affiliations

Affiliations

  • 1 1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2].
  • 2 1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3].
  • 3 1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
  • 4 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
  • 5 1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
  • 6 NE-CAT APS, Building 436E, Argonne National Lab, 9700 S.Cass Avenue, Argonne, Illinois 60439, USA.
  • 7 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
  • 8 1] Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3 [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
  • 9 MannKind Corporation, 28903 North Avenue Paine, Valencia, California 91355, USA.
  • 10 NanoTemper Technologies, Inc., 395 Oyster Point Boulevard, Suite 135, South San Francisco, California 94080, USA.
  • 11 1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
PMID: 25164867 DOI: 10.1038/ncomms5202
Abstract

Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12399
    98.33%, IRE1 Inhibitor