Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Stokes, Michael; Surman, M. D.; Calvo, Veronica; Surguladze, David; Li, Anhu; Gasparek, Jennifer; Betzenhauser, Matthew J.; Zhu, Guangyu; Du, Hongyin; Rigby, Alan C.; Mulvihill, Mark J.

doi:10.3390/pharmaceutics14102233

Cited by 7 publications

(16 citation statements)

References 27 publications

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“…First, because of the early neonatal lethality of Eif2ak3-/- mice and the challenges of generating timed, tissue conditional deletions on the NOD background, our study utilized pharmacologic inhibition of PERK in mice in vivo. Although our scRNA-Seq studies are consistent with PERK inhibition in β cells and the target specificity across kinome has been previously established (30), they do not fully exclude the potential for off-target responses. Additionally, our findings do not rule out a role for PERK in other cell types (e.g., immune cells or exocrine cells) that contribute to T1D pathogenesis.…”

Section: Discussionsupporting

confidence: 51%

“…In this study, we interrogated the PERK arm of the UPR pathway in the context of autoimmune diabetes. Because the genetic knockout of PERK in mice is known to result in endocrine and exocrine dysfunction during pancreas formation and maturation, we leveraged use of a recently described PERK inhibitor, HC-5770 (30). Our results show that (a) inhibition of PERK during a period of β cell ER stress/PERK hyperactivity in NOD mice reduces insulitis, preserves β cell mass, and delays the development of diabetes, (b) gene expression patterns in β cells following PERK inhibition are consistent with reductions in the UPR and PERK response, and (c) inhibition of PERK activity augments the immune checkpoint protein PD-L1 through stabilization mediated by GOLM1.In early T1D, β cells are exposed to inflammation, putative viral infections, hypoxia/ischemia, and impaired nutrient handling (resulting from insulin deficiency) (46–48).…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the role of PERK in β cell dysfunction in vivo, we made use of HC-5770, a recently described PERK inhibitor noted for its high selectivity and in vivo stability in mice (previously characterized as Cmpd26 in (30)). Initial pharmacokinetic and pharmacodynamic (PK/PD) analyses were performed to confirm in vivo PERK inhibition in mouse pancreas and to identify appropriate doses for further study.…”

Section: Pharmacokinetic and Pharmacodynamic Assessment Of The Perk I...mentioning

confidence: 99%

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Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Muralidharan,

Huang,

Enriquez

et al. 2023

Preprint

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Prevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to temporarily halt protein production and redirect energy towards cellular survival. We hypothesized that activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the unfolded protein response and PERK signaling pathways as well as alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice show a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetic and Pharmacodynamic Assessment Of The Perk I...mentioning

confidence: 99%

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Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Muralidharan,

Huang,

Enriquez

et al. 2023

Preprint

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“…The discovery and characterization of a highly potent and selective series of PERK inhibitors were recently reported. During this work, due to the high degree of homology of the kinase domain between PERK and GCN2, several enzymatic and cellular GCN2 in vitro assays were developed, to serve as counter screens to assess selectivity as part of the drug discovery cascade.…”

Section: Resultsmentioning

confidence: 99%

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator

Thomson,

Aicher,

Cheng

et al. 2024

J. Med. Chem.

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A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

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“…IC50 value of positive control 1 is 4 nM(Smith et al 2015). b The PERK IC50 value of positive control 2 is 2.2 nM(Stokes et al 2022). …”

mentioning

confidence: 99%

Extraction, rapid preparation and neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir.

Xu,

Dai,

Huang

et al. 2024

Natural Product Research

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Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%.Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM.

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Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Cited by 7 publications

References 27 publications

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator

Extraction, rapid preparation and neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir.

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