Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscale<i>in silico</i>approach

Mahdizadeh, Sayyed Jalil; Carlesso, Antonio; Eriksson, Leif A.

doi:10.1039/d0ra01895c

Cited by 5 publications

(5 citation statements)

References 51 publications

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“…Mahdizadeh et al reported the ability of a compound named MKC9989 to inhibition of IRE1. Their results revealed that this compound could target K907 of IRE1 selectively and inhibit it [38]. Carlesso and Eriksson also examined the activity of MKC9989 against 23 Lysine residues of IRE1 and found that the compound could only construct strong interactions with two of these residues, including Lys907 and Lys599 [39].…”

Section: Drug Binding To Ire1mentioning

confidence: 99%

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer

Poustforoosh,

Faramarz,

Nematollahi

et al. 2023

Drug Res (Stuttg)

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Background Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a key role in cancer progression. The aggregation of incorrectly folded proteins in the ER generates ER stress, which in turn activates the UPR as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1 (IRE1) is the most evolutionary conserved ER stress sensor, which plays a pro-tumoral role in various cancers. Targeting its’ active sites is one of the most practical approaches for the treatment of cancers. Objective In this study, we aimed to use the structure of 4μ8C as a template to produce newly designed compounds as IRE1 inhibitors. Methods Various functional groups were added to the 4μ8C, and their binding affinity to the target sites was assessed by conducting a covalent molecular docking study. The potential of the designed compound for further in vitro and in vivo studies was evaluated using ADMET analysis. Results Based on the obtained results, the addition of hydroxyl groups to 4μ8C enhanced the binding affinity of the designed compound to the target efficiently. Compound 17, which was constructed by the addition of one hydroxyl group to the structure of 4μ8C, can construct a strong covalent bond with Lys907. The outcomes of ADMET analysis indicated that compound 17 could be considered a drug-like molecule. Conclusion Our results revealed that designed compound 17 could inhibit IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of IRE1 and introduces a promising therapeutic strategy for cancer treatment.

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Section: Drug Binding To Ire1mentioning

confidence: 99%

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer

Poustforoosh,

Faramarz,

Nematollahi

et al. 2023

Drug Res (Stuttg)

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“…Gaining pharmacological control over IRE1 activities has been the focus of several anticancer drug development strategies, and these can be divided into two main approaches: (i) inhibiting IRE1 activity to impair adaptability of tumor cells to challenging tumor microenvironment and (ii) activating or hyperactivating IRE1 to initiate its RIDD that leads to cell death. Furthermore, downstream IRE1 signaling components have also been shown to be of interest to drug discovery programs (Marciniak et al 2022 ; Raymundo et al 2020 ; Carlesso et al 2019 , 2020 ; Mahdizadeh et al 2020 , 2021 ; Doultsinos et al 2021 ; Mercado and Hetz 2017 ; Dufey et al 2020 ).…”

Section: Pharmacological Targeting Of Ire1 In Anticancer Approachesmentioning

confidence: 99%

Dual RNase activity of IRE1 as a target for anticancer therapies

Bartoszewska,

Sławski,

Collawn

et al. 2023

J. Cell Commun. Signal.

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The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic. Graphical abstract

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“…Additional analogous HAA inhibitors sharing different scaffolds of naphthalene [75,76], single-ring and biphenyl [75], coumarin [79], and chromenone [80] were also identified and proved to be potent inhibitors of IRE1 RNase activity. The mystery behind the high selectivity of HAA inhibitors toward one of the specific Lysine residues (Lys907) among all 23 Lysine residues of IRE1 has been deciphered in two recent studies [81,82]. In a first study [82], the interaction of MKC9989 molecules with two buried Lysine residues (Lys599 and Lys907) and two solvent-exposed ones (Lys656 and Lys799) as representative residues of IRE1 (PDB ID 4PL3), was investigated by means of molecular docking and extensive MD simulations.…”

Section: Ire1 Rnase Domain Covalent Ligandsmentioning

confidence: 99%

“…Since Lys599 is located within the kinase pocket, an endogenous ligand like ATP is expected to strongly compete with the inhibitors in binding to Lys599, which justifies their inactivity in IRE1 kinase inhibition. This was followed by a detailed exploration of the selectivity of the MKC9989 inhibitor towards residue Lys907 using multiscale in silico techniques including Multi-Conformation Continuum Electrostatics (MCCE) simulations, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations, covalent docking, and MD simulations [81]. According to these results, Lys907 is completely deprotonated within its hydrophobic pocket, which is an essential requirement for the initiation of the Schiff base reaction with the aldehyde moiety of the HAA molecules.…”

Section: Ire1 Rnase Domain Covalent Ligandsmentioning

confidence: 99%

Structural and molecular bases to IRE1 activity modulation

Langlais

Pelizzari-Raymundo

Mahdizadeh

et al. 2021

Biochemical Journal

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The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

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Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscalein silicoapproach

Abstract: The high selectivity of inhibitor MKC9989 towards Lys907 of IRE1α is explained by the unique pKa properties of the lysine.

Cited by 5 publications

References 51 publications

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer

Dual RNase activity of IRE1 as a target for anticancer therapies

Structural and molecular bases to IRE1 activity modulation

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