A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

被引：17

作者：

Pelizzari-Raymundo, Diana ^{[1
,2
]}

Doultsinos, Dimitrios ^{[1
,2
]}

Pineau, Raphael ^{[1
,2
]}

Sauzay, Chloe ^{[1
,2
]}

Koutsandreas, Thodoris ^{[4
,5
]}

Langlais, Timothy ^{[3
]}

Carlesso, Antonio ^{[6
]}

Gkotsi, Elena ^{[4
,5
]}

Negroni, Luc ^{[7
]}

Avril, Tony ^{[1
,2
]}

Chatziioannou, Aristotelis ^{[4
,5
]}

Chevet, Eric ^{[1
,2
]}

Eriksson, Leif A. ^{[6
]}

Guillory, Xavier ^{[1
,2
,3
]}

机构：

[1] Univ Rennes, INSERM U1242, Rennes, France

[2] Ctr Lutte Canc Eugene Marquis, Rennes, France

[3] Univ Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France

[4] E Nios PC, Kallithea Athens, Greece

[5] Biomed Res Fdn Acad Athens, Ctr Syst Biol, Athens, Greece

[6] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden

[7] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire IGBMC, Prote platform, CNRS UMR7104,INSERM U964, Illkirch Graffenstaden, France

来源：

ISCIENCE | 2023年 / 26卷 / 05期

基金：

欧盟地平线“2020”; 瑞典研究理事会;

关键词：

UNFOLDED PROTEIN RESPONSE; REQUIRING ENZYME 1-ALPHA; ENDOPLASMIC-RETICULUM; STRESS-RESPONSE; IRE1-ALPHA; ANGIOGENESIS; PENETRATION; SIMILARITY; PATHWAYS; INVASION;

D O I：

10.1016/j.isci.2023.106687

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress over-come by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood-brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.

引用

页数：24

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