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

Mario Sanches, Nicole M. Duffy, Manisha Talukdar, Nero Thevakumaran, David Chiovitti, Marella D. Canny, Kenneth Lee, Igor Kurinov, David Uehling, Rima Al-awar, Gennadiy Poda, Michael Prakesch, Brian Wilson, Victor Tam, Colleen Schweitzer, Andras Toro, Julie L. Lucas, Danka Vuga, Lynn Lehmann, Daniel Durocher, Qingping Zeng, John B. Patterson () and Frank Sicheri ()
Additional contact information
Mario Sanches: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Nicole M. Duffy: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Manisha Talukdar: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Nero Thevakumaran: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
David Chiovitti: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Marella D. Canny: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Kenneth Lee: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Igor Kurinov: NE-CAT APS, Building 436E, Argonne National Lab
David Uehling: Drug Discovery Program, Ontario Institute for Cancer Research
Rima Al-awar: Drug Discovery Program, Ontario Institute for Cancer Research
Gennadiy Poda: Drug Discovery Program, Ontario Institute for Cancer Research
Michael Prakesch: Drug Discovery Program, Ontario Institute for Cancer Research
Brian Wilson: Drug Discovery Program, Ontario Institute for Cancer Research
Victor Tam: MannKind Corporation
Colleen Schweitzer: MannKind Corporation
Andras Toro: MannKind Corporation
Julie L. Lucas: MannKind Corporation
Danka Vuga: MannKind Corporation
Lynn Lehmann: NanoTemper Technologies, Inc.
Daniel Durocher: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Qingping Zeng: MannKind Corporation
John B. Patterson: MannKind Corporation
Frank Sicheri: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5202

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