Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1

Chintha, Chetan; Carlesso, Antonio; Gorman, Adrienne M.; Samali, Afshin; Eriksson, Leif A.

doi:10.1039/c9ra08047c

Cited by 21 publications

(8 citation statements)

References 38 publications

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“…et al For GSK'157 suggested a good selectivity profile of the compound, even though RIPK1 was not included in the panel. In this study we confirmed the hypothesis that the potency and selectivity for RIPK1 could be increased by derivatising the corresponding para-position of the GSK'157 pyridinyl ring (Axten et al, 2013;Chintha et al, 2019). In addition, based on the mode of interaction of While for the latter the binding site is slightly solvent-exposed, for RIPK1 the pocket is buried, featuring a more hydrophobic profile due to the presence of three Leu, two Val, and Met (not shown in detail).…”

Section: Discussionsupporting

confidence: 82%

“…The reported structure-activity relationship (SAR) suggested that derivatisation of the corresponding para-position of the pyridinyl ring could reduce affinity for PERK (Axten et al, 2012;. Moreover, recent molecular modelling studies confirmed the different nature of the C-alpha helix domain in RIPK1 with the presence of an additional lipophilic pocket compared to PERK (Chintha et al, 2019). We investigated the structural differences between PERK and RIPK1 and we verified the presence of an extra pocket with additional space to place the para-substituent.…”

Section: Introductionmentioning

confidence: 76%

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From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

et al. 2023

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Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) emerged as an important driver of inflammation and, consequently, inflammatory pathologies. The enzymatic activity of RIPK1 is known to indirectly promote inflammation by triggering cell death, in the form of apoptosis, necroptosis and pyroptosis. Small molecule Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors have therefore recently entered clinical trials for the treatment of a subset of inflammatory pathologies. We previously identified GSK2656157 (GSK’157), a supposedly specific inhibitor of protein kinase R (PKR)-like ER kinase (PERK), as a much more potent type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitor. We now performed further structural optimisation on the GSK’157 scaffold in order to develop a novel class of more selective Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors. Based on a structure-activity relationship (SAR) reported in the literature, we anticipated that introducing a substituent on the para-position of the pyridinyl ring would decrease the interaction with PERK. Herein, we report a series of novel GSK’157 analogues with different para-substituents with increased selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1. The optimisation led to UAMC-3861 as the best compound of this series in terms of activity and selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1 over PERK. The most selective compounds were screened in vitro for their ability to inhibit RIPK1-dependent apoptosis and necroptosis. With this work, we successfully synthesised a novel series of potent and selective type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors based on the GSK’157 scaffold.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 76%

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

et al. 2023

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“…We then asked which one or a combination of the three ER stress-responding pathways ( Ron and Walter, 2007 ) were involved in Alternol treatment-induced ER stress. We utilized pathway-selective pharmacological inhibitors for these three pathways, IRE1α inhibitor MKC8866 ( Sheng et al, 2019 ), PERK inhibitor AMG44 ( Chintha et al, 2019 ), and ATF6 inhibitor CEAPIN-A7 ( Xue et al, 2021 ) to determine their involvement in Alternol-induced ER stress response ( Figure 3D ). Our results showed that pretreatment with AMG44 reduced the Alternol-induced ATF4 expression while MKC8866 pretreatment suppressed Alternol-induced XBP1s expression.…”

Section: Resultsmentioning

confidence: 99%

Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death

Liu,

He,

et al. 2024

Front. Pharmacol.

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Background: Alternol is a small molecular compound isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. This study conducted a comprehensive investigation to explore the mechanisms involved in Alternol-induced immunogenic cell death.Methods: Prostate cancer PC-3, C4-2, and 22RV1 were used in this study. Alternol interaction with heat shock proteins (HSP) was determined using CETSA assay. Alternol-regulated ER stress proteins were assessed with Western blot assay. Extracellular adenosine triphosphate (ATP) was measured using ATPlite Luminescence Assay System.Results: Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data represented a potential cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent (ER) stress responses via R-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α). The double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress responses cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death.Conclusion: Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, leading to immunogenic cell death.

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“…Similarly, several reports have shown that GSK2606414 can act in a PERK-independent manner. GSK2606414 was demonstrated to be a potent inhibitor of RIPK1 kinase [50,51]. GSK2606414 was also able to inhibit KIT tyrosine kinase activity and enhance endocytosis and lysosomal degradation [52].…”

Section: Discussionmentioning

confidence: 99%

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs

Yu,

Xu,

Wang

et al. 2023

Biomedicines

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Colorectal cancer is a common malignant tumor. A major factor in the high mortality rate of colorectal cancer is the emergence of multidrug resistance (MDR). Overexpression of the ABCG2 gene in cancer cells directly leads to MDR. Finding new inhibitors of ABCG2 may be an effective way to overcome drug resistance. We found that the compound GSK2606414 enhanced the sensitivity of the ABCG2 substrate to the chemotherapeutic drugs mitoxantrone and doxorubicin in ABCG2-overexpressing multidrug-resistant colorectal cancer cells by increasing their intracellular accumulation without affecting the protein expression of ABCG2. Molecular docking experiments predicted that GSK2606414 could stably bind in the drug-binding pocket of ABCG2. In conclusion, GSK2606414 can sensitize ABCG2-overexpressed multidrug-resistant colorectal cancer cells to chemotherapy drugs and can be used as a potential inhibitor of ABCG2.

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Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1

Abstract: Molecular modelling explains the lack of selectivity for inhibitors GSK2606414 and GSK2656157, as compared to inhibitor AMG44.

Cited by 21 publications

References 38 publications

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors

Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs

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