Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response

Amarasinghe, Kosala N.; Pelizzari-Raymundo, Diana; Carlesso, Antonio; Chevet, Éric; Eriksson, Leif A.; Mahdizadeh, Sayyed Jalil

doi:10.1016/j.csbj.2022.03.029

Cited by 9 publications

(20 citation statements)

References 49 publications

(64 reference statements)

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“…The lysine residue is not present in the same position in RNase L, making such Lysine-based covalent-targeting approach selective for IRE1. Furthermore, a docking study addressing the dimer interface of the RNase domain identified neomycin (IC 50 0.33 μM) as an IRE1 inhibitor …”

Section: Small Molecules Targeting Human Ribonucleasesmentioning

confidence: 99%

“…Furthermore, a docking study addressing the dimer interface of the RNase domain identified neomycin (IC 50 0.33 μM) as an IRE1 inhibitor. 112 ■ BIFUNCTIONAL MOLECULES TARGETING RNASES Bifunctional Dicer Inhibitors. An emerging approach to target ribonucleases is the design of bifunctional molecules to activate, bind, or inhibit an RNase in a specific context (Figure 7).…”

Section: Viral Rnasesmentioning

confidence: 99%

“…Thus, IRE1 activity is associated with cancer progression, aggressiveness, and poor prognosis. − In addition to being studied as an anticancer target, IRE1 has also been implicated in diabetes and angiogenesis regulation. , IRE1-targeting modulators were developed against the kinase and RNase domains (Figure ). Similar to RNase L, reported kinase inhibitors were repurposed for IRE1 inhibition. , Interestingly, some kinase inhibitors did not inhibit RNase function but activated IRE1 RNase activity instead. ,, In general, type I kinase inhibitors stabilized the active kinase conformation and activated IRE1 RNase activity promoting oligomerization, while type II kinase inhibitors stabilized the inactive kinase conformation and inhibited RNase enzymatic activities. ,, Assays for the identification of IRE1 modulators comprise splicing assays, fluorescence-based cleavage assays using fluorophore- and quencher-labeled XBP1 RNA substrate, and phosphorylation assays that focused on kinase activity instead of RNase activity. ,,, IRE1 inhibitor imidazo[1,5-α]pyrazine-8-amine compound 3 was identified based on screening of known type II kinase inhibitors, and further modification led to the development of compounds KIRA6 and KIRA7. ,, Both KIRA6 and KIRA7 were potent inhibitors in biochemical and cellular evaluations, but a photoaffinity labeling approach revealed low selectivity of the imidazo[1,5-α]pyrazine-8-amine scaffold toward IRE1. ,, The sulfonamide KIRA8 was an optimized hit with an IC 50 of 0.014 μM in biochemical assays, but it did not affect cancer cell viability when screened against more than 300 different cancer cell lines. , GSK2850163 is a screening-identified selective IRE1 inhibitor that bound to the kinase domain and displaced the kinase activation loop, thereby inhibiting RNase activity with an IC 50 of 200 nM . Compound 31 was further identified as an IRE1-selective inhibitor (IC 50 80 nM) that stabilized the inactive kinase conformation allosterically .…”

Section: Small Molecules Targeting Human Ribonucleasesmentioning

confidence: 99%

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Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

Borgelt

2023

ACS Chem. Biol.

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Ribonucleases (RNases) cleave and process RNAs, thereby regulating the biogenesis, metabolism, and degradation of coding and noncoding RNAs. Thus, small molecules targeting RNases have the potential to perturb RNA biology, and RNases have been studied as therapeutic targets of antibiotics, antivirals, and agents for autoimmune diseases and cancers. Additionally, the recent advances in chemically induced proximity approaches have led to the discovery of bifunctional molecules that target RNases to achieve RNA degradation or inhibit RNA processing. Here, we summarize the efforts that have been made to discover small-molecule inhibitors and activators targeting bacterial, viral, and human RNases. We also highlight the emerging examples of RNase-targeting bifunctional molecules and discuss the trends in developing such molecules for both biological and therapeutic applications.

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Section: Small Molecules Targeting Human Ribonucleasesmentioning

confidence: 99%

Section: Viral Rnasesmentioning

confidence: 99%

Section: Small Molecules Targeting Human Ribonucleasesmentioning

confidence: 99%

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Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

Borgelt

2023

ACS Chem. Biol.

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“…Small-molecule mediated modulation of IRE1 activity has been achieved by compounds targeting either the ATP-binding kinase pocket, the RNase domain 4 or allosteric sites 5 . Studies have demonstrated that Kinase inhibiting RNase attenuators (KIRAs) that binds the kinase pocket have a direct inhibitory effect on IRE1 RNase activity 6,7 .…”

Section: Introductionmentioning

confidence: 99%

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

Pelizzari-Raymundo

Doultsinos

Pineau

et al. 2023

Preprint

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Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It 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 such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells can rely on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of novel IRE1 inhibitors identified through the structural exploration of the IRE1 kinase domain. We characterized the candidates in vitro and in cellular models and showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). We next selected a Blood-Brain Barrier (BBB) permeable inhibitor (Z4P) among these molecules and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. The hit compound disclosed in this study 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.

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“…IRE1 RNase domain then channels the functional outputs of IRE1 by unconventionally splicing XBP1 mRNA to produce XBP1s, a potent transcription factor, or by cleaving a subset of mRNAs and miRNAs in a process called Regulated IRE1 Dependent Decay (of RNA). Inhibiting IRE1 activity can thus be achieved by compounds targeting the ATP-binding kinase pocket, the RNase domain (3) or targeting other domains (4). Studies have demonstrated that Kinase inhibiting RNase attenuators (KIRAs) may have an inhibitory effect on IRE1 RNase activity (5,6).…”

Section: Introductionmentioning

confidence: 99%

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

Pelizzari-Raymundo

Doultsinos

Pineau

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized the candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.

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Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response

Cited by 9 publications

References 49 publications

Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

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