Pharmacological Targeting of IRE1 in Cancer

Diana Pelizzari Raymundo; Dimitrios Doultsinos; Xavier Guillory; Antonio Carlesso; Leif A Eriksson; Eric Chevet

doi:10.1016/j.trecan.2020.07.006

Pharmacological Targeting of IRE1 in Cancer

Trends Cancer. 2020 Dec;6(12):1018-1030. doi: 10.1016/j.trecan.2020.07.006. Epub 2020 Aug 26.

Authors

Diana Pelizzari Raymundo¹, Dimitrios Doultsinos¹, Xavier Guillory², Antonio Carlesso³, Leif A Eriksson⁴, Eric Chevet⁵

Affiliations

¹ Proteostasis and Cancer Team, INSERM U1242, COSS Laboratory, Université de Rennes, Rennes, France; Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
² Institut des Science Chimiques de Rennes, CNRS UMR6226, Université de Rennes, Rennes, France.
³ Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
⁴ Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden. Electronic address: leif.eriksson@chem.gu.se.
⁵ Proteostasis and Cancer Team, INSERM U1242, COSS Laboratory, Université de Rennes, Rennes, France; Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France. Electronic address: eric.chevet@inserm.fr.

PMID: 32861679
DOI: 10.1016/j.trecan.2020.07.006

Abstract

IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.

Keywords: IRE1; activators; endoplasmic reticulum; inhibitors; unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Allosteric Regulation / drug effects
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Endoplasmic Reticulum Stress / drug effects
Endoplasmic Reticulum Stress / genetics
Endoribonucleases / antagonists & inhibitors*
Endoribonucleases / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / pathology
Protein Domains / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proteostasis / drug effects
Proteostasis / genetics
Signal Transduction / drug effects
Signal Transduction / genetics
Unfolded Protein Response / drug effects
Unfolded Protein Response / genetics

Substances

Protein Kinase Inhibitors
ERN1 protein, human
Protein Serine-Threonine Kinases
Endoribonucleases