Structure-Based Drug Discovery of IRE1 Modulators

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2022 Jan 5

PMID 34985708

Authors

Diana Pelizzari Raymundo

Leif A Eriksson

Eric Chevet

Xavier Guillory

Affiliations

Soon will be listed here.

Abstract

IRE1α (inositol-requiring enzyme 1 alpha, referred to IRE1 hereafter) is an Endoplasmic Reticulum (ER) resident transmembrane enzyme with cytosolic kinase/RNAse activities. Upon ER stress IRE1 is activated through trans-autophosphorylation and oligomerization, resulting in a conformational change of the RNase domain, thereby promoting two signaling pathways: i) the non-conventional splicing of XBP1 mRNA and ii) the regulated IRE1-dependent decay of RNA (RIDD). IRE1 RNase activity has been linked to diverse pathologies such as cancer or inflammatory, metabolic, and degenerative diseases and the modulation of IRE1 activity is emerging as an appealing therapeutic strategy against these diseases. Several modulators of IRE1 activity have been reported in the past, but none have successfully translated into the clinics as yet. Based on our expertise in the field, we describe in this chapter the approaches and protocols we used to discover novel IRE1 modulators and characterize their effect on IRE1 activity.

References

Hetz C, Chevet E, Oakes S . Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015; 17(7):829-38. PMC: 5546321. DOI: 10.1038/ncb3184. View

Maurel M, Chevet E, Tavernier J, Gerlo S . Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 2014; 39(5):245-54. DOI: 10.1016/j.tibs.2014.02.008. View

Guydosh N, Kimmig P, Walter P, Green R . Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in . Elife. 2017; 6. PMC: 5650469. DOI: 10.7554/eLife.29216. View

Sheng X, Nenseth H, Qu S, Kuzu O, Frahnow T, Simon L . IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun. 2019; 10(1):323. PMC: 6345973. DOI: 10.1038/s41467-018-08152-3. View

Lhomond S, Avril T, Dejeans N, Voutetakis K, Doultsinos D, McMahon M . Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol Med. 2018; 10(3). PMC: 5840541. DOI: 10.15252/emmm.201707929. View

Zhao N, Cao J, Xu L, Tang Q, Dobrolecki L, Lv X . Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest. 2018; 128(4):1283-1299. PMC: 5873887. DOI: 10.1172/JCI95873. View

Le Reste P, Pineau R, Voutetakis K, Samal J, Jegou G, Lhomond S . Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo. Cancer Lett. 2020; 494:73-83. DOI: 10.1016/j.canlet.2020.08.028. View

Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J . The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017; 18(5):519-529. DOI: 10.1038/ni.3709. View

10.

Lebeaupin C, Vallee D, Rousseau D, Patouraux S, Bonnafous S, Adam G . Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology. 2018; 68(2):515-532. DOI: 10.1002/hep.29847. View

11.

Medinas D, Gonzalez J, Falcon P, Hetz C . Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2017; 10:216. PMC: 5496948. DOI: 10.3389/fnmol.2017.00216. View

12.

Kiskinis E, Sandoe J, Williams L, Boulting G, Moccia R, Wainger B . Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell. 2014; 14(6):781-95. PMC: 4653065. DOI: 10.1016/j.stem.2014.03.004. View

14.

Duran-Aniotz C, Cornejo V, Espinoza S, Ardiles A, Medinas D, Salazar C . IRE1 signaling exacerbates Alzheimer's disease pathogenesis. Acta Neuropathol. 2017; 134(3):489-506. DOI: 10.1007/s00401-017-1694-x. View

15.

Martinon F, Chen X, Lee A, Glimcher L . TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010; 11(5):411-8. PMC: 3113706. DOI: 10.1038/ni.1857. View

16.

Chopra S, Giovanelli P, Alvarado-Vazquez P, Alonso S, Song M, Sandoval T . IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science. 2019; 365(6450). DOI: 10.1126/science.aau6499. View

17.

Tufanli O, Akillilar P, Acosta-Alvear D, Kocaturk B, Onat U, Hamid S . Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc Natl Acad Sci U S A. 2017; 114(8):E1395-E1404. PMC: 5338400. DOI: 10.1073/pnas.1621188114. View

18.

Wang L, Perera B, Hari S, Bhhatarai B, Backes B, Seeliger M . Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat Chem Biol. 2012; 8(12):982-9. PMC: 3508346. DOI: 10.1038/nchembio.1094. View

19.

Feldman H, Tong M, Wang L, Meza-Acevedo R, Gobillot T, Lebedev I . Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands. ACS Chem Biol. 2016; 11(8):2195-205. PMC: 4992410. DOI: 10.1021/acschembio.5b00940. View

20.

Pelizzari Raymundo D, Doultsinos D, Guillory X, Carlesso A, Eriksson L, Chevet E . Pharmacological Targeting of IRE1 in Cancer. Trends Cancer. 2020; 6(12):1018-1030. DOI: 10.1016/j.trecan.2020.07.006. View

21.

Hetz C, Axten J, Patterson J . Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol. 2019; 15(8):764-775. DOI: 10.1038/s41589-019-0326-2. View

22.

Sterling T, Irwin J . ZINC 15--Ligand Discovery for Everyone. J Chem Inf Model. 2015; 55(11):2324-37. PMC: 4658288. DOI: 10.1021/acs.jcim.5b00559. View