GSK2606414 / GSK, Institute of Cancer Research, Dartmouth College - LARVOL DELTA

The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes. (PubMed, Pharmacol Rep) - No abstract available

Journal • CNS Disorders • Developmental Disorders • Metabolic Disorders • Psychiatry

Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers. (PubMed, Biomedicines) - "Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • ATF4 • EIF2B4 • PPP1R15A

Integrated Stress Response (ISR) Modulators in Vascular Diseases. (PubMed, Cells) - "We further discuss pharmacological ISR modulators-including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157-which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention."

Journal • Review • Atherosclerosis • Cardiovascular • Hematological Disorders • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Thrombosis • ATF4

Baicalin Alleviates LPS-Induced Apoptosis of Periodontal Ligament Cells Via Inhibiting Endoplasmic Reticulum Stress. (PubMed, Int Dent J) - "BA shows therapeutic potential for periodontitis by inhibiting ER stress - mediated apoptosis and protecting periodontal tissue."

IO biomarker • Journal • Dental Disorders • Periodontitis • ATF4 • ATF6 • BAX • BCL2 • CASP3 • HSPA5

Endoplasmic Reticulum Stress Mediates Axon Initial Segment Shortening: Implications for Diabetic Brain Complications. (PubMed, J Mol Neurosci) - "Co-exposure to a PERK-specific inhibitor GSK2606414 prevented AIS shortening induced by tunicamycin. These results demonstrate ER stress is sufficient and necessary for AIS shortening in vitro. Our findings identify ER stress and AIS shortening as potential therapeutic targets in T2DM-related cognitive impairment."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

KLF10-IN-1 Attenuates RPE Cell Apoptosis and Experimental Diabetic Retinopathy Via the KLF10/PERK/eIF2α/ATF4/CHOP Pathway. (PubMed, Invest Ophthalmol Vis Sci) - "The PERK pathway was activated by CCT020312 and inhibited by GSK2606414 for rescue experiments...KLF10 is upregulated in DR model mice and high-glucose/hypoxia-exposed RPE cells and modulates apoptosis and ER stress through the PERK/eIF2α/ATF4/CHOP pathway. KLF10-IN-1 has protective effects, suggesting its potential for early DR treatment."

Journal • Diabetes • Diabetic Retinopathy • Inflammation • Retinal Disorders • ATF4 • KLF10

The EIF2α-PERK Signaling Pathway Mediates Manganese Exposure-Induced A1-Type Astrocytes Activation via Endoplasmic Reticulum Stress. (PubMed, Toxics) - "Suppression of astrocytic PERK, using either ISRIB or GSK2606414, alleviates Mn-induced ER stress and A1 activation, which in turn mitigates the motor deficits induced by Mn exposure. These findings reveal that inhibition of PERK can ameliorate Mn-induced neurotoxicity by suppressing astrocyte activation and preserving organelle homeostasis, offering a potential therapeutic strategy to mitigate the harmful effects of Mn toxicity."

Journal • CNS Disorders • Inflammation

CK2α Regulates Endoplasmic Reticulum Stress-Mediated Mitophagy via the PERK/ATF4/CHOP Pathway in Rotenone-Treated SH-SY5Y Cells. (PubMed, Mol Neurobiol) - "Interestingly, treatment of cells with the PERK inhibitor GSK2606414 also resulted in increased PINK1/Parkin-mediated mitophagy...These findings suggest that CK2α plays a key role in regulating the ER stress response and PERK-dependent PINK1/Parkin-mediated mitophagy in our rotenone-induced apoptosis model. This study highlights the therapeutic potential of CK2α signal regulation for treating diseases driven by ER stress and mitochondrial dysfunction, offering a promising avenue for future research."

Journal • Metabolic Disorders • ATF4

Mechanism of endoplasmic reticulum stress-induced endothelial cell ferroptosis in trichloroethylene-induced mouse kidney injury. (PubMed, Toxicol Res) - "The PERK inhibitor GSK2606414 can suppress ferroptosis via the Nrf2/HO-1 signaling pathway and reduce trichloroethylene-induced renal injury. In conclusion, TCE sensitization activates ERS through the PERK/eIF2α/ATF4 pathway, with PERK subsequently mediating ferroptosis of renal vascular endothelial cells via the Nrf2/HO-1 signaling pathway, thereby contributing to TCE-related immune kidney injury."

Journal • Preclinical • Dermatitis • Dermatology • Immunology • Renal Disease • ATF4

TGF-β1 Induces Endoplasmic Reticulum Stress-dependent Apoptosis in Human Placental Mesenchymal Stem Cells of Fetal Origin through PERK Signaling Pathway. (PubMed, Curr Stem Cell Res Ther) - "Our findings indicated that TGF-β1 induced ER stress-dependent apoptosis in fPMSCs through the PERK signaling pathway. These results offer insights into enhancing the therapeutic efficacy of fPMSCs by modulating TGF-β1-induced apoptosis."

Journal • Hematological Disorders • Immunology • ANXA5 • HSPA5 • TGFB1

Mycotoxin Alternariol Exposure Promotes Endoplasmic Reticulum Stress-induced Hepatotoxicity to Exacerbate Chronic Liver Injury. (PubMed, Environ Pollut) - "Pharmacological intervention studies demonstrated that both TUDCA (ER stress inhibitor) and GSK2606414 (PERK inhibitor) effectively mitigated AOH-induced cytotoxicity in hepatocytes. Thus, we delineate ER stress as central mechanism driving AOH-induced hepatotoxicity and validate PERK cascade inhibition as viable protective strategy. These findings fundamentally refine risk assessment framework for mycotoxin exposure while proposing novel molecular targets for therapeutic intervention against environmental hepatotoxicants."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • ATF4

The role and mechanism of gut microbial metabolite trimethylamine N-Oxide in the occurrence and development of right heart failure (ERS 2025) - "Right ventricular fibroblasts utilize the intrinsic TMA-FMO3-TMAO axis for localized TMAO production, activating the PERK-eIF2α-ATF4/CHOP pathway to promote fibrosis and exacerbate RHF progression."

Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ATF4 • COL1A1

Human umbilical cord mesenchymal stem cell -derived exosomes alleviated the toxic effects induced by lead on HK-2 cells via regulating the unfolded protein response. (PubMed, Ecotoxicol Environ Saf) - "Moreover, when GSK2606414 was employed to block the phosphorylation of PERK, the toxic effects of lead were also significantly alleviated. Hence, we conclude that hucMSC - exos can alleviate the toxicity of lead to HK-2 cells via interfering with the UPR, in which PERK plays a crucial role, and it may be a promising target for intervening in the toxicity of lead."

Journal • HSPA5

Mechanisms of sorafenib-induced cardiotoxicity: ER stress induces upregulation of ATF3, leading to downregulation of NDUFS1 expression and mitochondrial dysfunction. (PubMed, Front Pharmacol) - "These outcomes were supported by Western blot analysis and microscopic imaging, and were significantly mitigated following treatment with the ER stress inhibitor GSK2606414. Silencing ATF3 via siRNA partially restored mitochondrial function, suggesting a negative regulatory effect of ATF3 on NDUFS1 that contributes to sorafenib-induced mitochondrial impairment. Collectively, these results uncover a critical signaling cascade-PERK/eIF2α/ATF4/ATF3/NDUFS1-involved in sorafenib-mediated cardiotoxicity and point to ATF3 modulation as a promising target for preventing or reducing cardiac injury caused by this drug."

Journal • Cardiovascular • Metabolic Disorders • ATF3 • ATF4 • NDUFS1

Variant rs13045 reduces EIF2AK3 expression and inhibits pro-inflammatory cytokine secretion via the MAPK-ERK1/2 pathway in Kawasaki disease. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "EIF2AK3/rs13045 is a novel susceptibility locus for KD in the Southern Chinese population. Our findings reveal that EIF2AK3 upregulates pro-inflammatory cytokines, thereby promoting KD-associated vasculitis via the MAPK-ERK1/2 pathway. This discovery suggests EIF2AK3 as a potential therapeutic target for the management of KD."

Journal • Cardiovascular • Heart Failure • Inflammation • Vasculitis • CXCL8 • EIF2AK3 • IL1B • IL6 • PERK • TNFA

Inhibition of PERK pathway promotes TAMs M1 polarization and ER stress in Osteosarcoma cells hindering tumor progression. (PubMed, Int Immunopharmacol) - "Inhibition of the PERK pathway could exacerbate ER stress and promote apoptosis in osteosarcoma cells, while also altering the polarization state of TAMs from the immunosuppressive M2 phenotype to the anti-tumorigenic M1 phenotype, thereby disrupting tumor immunosuppression. This study provides a new perspective on the biological mechanisms of osteosarcoma and opens up a new direction for its therapeutic strategies."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Targeting the PERK/NRF2 Pathway: Enhancing cisplatin Efficacy in Resistant Ovarian Cancer Cells through MRP1 and ROS Modulation. (PubMed, Food Chem Toxicol) - "These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers."

Journal • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor • CASP12 • MSH3

The unfolded protein response influences therapy outcome and disease progression in chronic lymphocytic leukaemia. (PubMed, Sci Rep) - "The PERK inhibitor, GSK2606414, sensitised resistant, but not sensitive, HG-3 cells to fludarabine without affecting background cell viability or cytotoxicity induced by the BCL-2 inhibitor venetoclax. These findings identify the UPR as a novel determinant of therapy outcome and disease progression in CLL."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Endoplasmic reticulum stress of astrocytes in paraventricular nucleus of hypothalamus promotes ventricular electrical instability after acute myocardial infarction in rats. (PubMed, Front Cardiovasc Med) - "As a result, 24 h after AMI, PVN astrocytes underwent ER stress via PERK/CHOP pathway, which caused central inflammation, sympathetic neuron activation, and increased ventricular electrical activity instability. GSK2606414 microinjection into hypothalamus decreased sympathetic nerve excitement and VA occurrence in AMI rats by inhibiting ER stress of PVN astrocytes."

Journal • Preclinical • Cardiovascular • Inflammation • Myocardial Infarction • GFAP • IL6 • TNFA

A Protective Role for Endocannabinoids in Preventing Oxidative Stress in HCAECOxidative Stress in HCAEC (ENDO 2025) - "Likewise, the PERK inhibitor GSK2606414 prevented NRF2 induction by anandamide and tunicamycin while treatment with Ceapin A7 (an ATF6 inhibitor) or GSK2850163 (an IRE1α inhibitor) did not. In conclusion, endocannabinoid related ER stress augments production of antioxidant enzymes thereby highlighting the cross talk between ER stress and oxidative stress."

Oxidative stress • Cardiovascular • CNS Disorders • ATF6 • ERN1 • HMOX1 • NQO1 • PERK

TIME AND DOSE-DEPENDENT EFFECTS OF PERK INHIBITION IN A DUX4-R B- ACUTE LEUKEMIA CELL LINE (EHA 2025) - "We used pharmacological inhibitor of PERK, GSK2606414 (GSK) to perform MTS assay to quantify cell proliferation alone, and in combination with chemotherapeutic drug Daunorubicin (DNR). Our findings highlight the potential of PERK inhibition to enhance the efficacy of daunorubicin in B-acute leukemia cells, revealing cell line-specific mechanistic differences in response. The combination treatment significantly sensitized NALM6 and Reh cells to daunorubicin, as evidenced by reduced cell viability, altered cell cycle dynamics, and increased apoptosis. While NALM6 cells exhibited enhanced necrosis and G1/S phase arrest, Reh cells showed increased apoptosis with sub-G1 enrichment, suggesting distinct cellular adaptations to the combined treatment."

Preclinical • Hematological Malignancies • Leukemia • Oncology • ANXA5 • DUX4

Transcriptional regulation of solute carrier family 6 member 9 gene. (PubMed, Mol Biol Rep) - "The ATF4-binding sequence found near the transcription start site of the Slc6a9 gene is highly conserved among species and the element is functional in the PERK-ATF4 system. This study will help elucidate Slc6a9-mediated regulation of intracellular and extracellular amino acid homeostasis under pathophysiological conditions."

Journal • ATF4 • ATF6 • DDIT3 • ERN1 • HSPA5

Perks of Inhibiting PKR- Like Endoplasmic Reticulum Kinase (PERK)- Regulation of Cytokine Storm During IAV Infection (ATS 2025) - "Pro-inflammatory cytokines released under the control of P-PERK were identified using an inhibitor, GSK2606414 (PERKi) that inhibits PERK activation... These results suggest PERK's involvement in overt cytokine release during IAV infection."

Cytokine storm • Infectious Disease • Influenza • Respiratory Diseases • CCL20 • CXCL8 • IL6 • PERK

Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. (PubMed, Hereditas) - "Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC."

Clinical data • Journal • Hepatocellular Cancer • Oncology • Solid Tumor

NR4A1 deficiency promotes carotid plaque vulnerability by activating integrated stress response via targeting Bcat1. (PubMed, Cell Mol Life Sci) - "ISR inhibitor GSK2606414 or Bcat1 inhibitor ERG240 significantly ameliorated atherosclerotic plaque formation and increased plaque stability...These findings suggest that NR4A1 deficiency exacerbates vulnerable plaque by activating ISR via targeting Bcat1. The NR4A1/Bcat1/ISR axis is therefore an important therapeutic target for stabilizing atherosclerotic plaque."

Journal • Atherosclerosis • Cardiovascular • Hematological Disorders • Inflammation • Ischemic stroke • Thrombosis • APOE • BCAT1 • NR4A1