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

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

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

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

Acrylamide Induces Antiapoptotic Autophagy and Apoptosis by Activating PERK Pathway in SH-SY5Y Cells. (PubMed, Toxics) - "Then, a PERK inhibitor and autophagy inhibitor, GSK2606414 and 3-methyladenine (3-MA), were used separately to inhibit the PERK pathway and autophagy activation in SH-SY5Y cells under ACR treatment...Under 3-MA and ACR treatment, the autophagy inhibition deteriorated apoptosis in SH-SY5Y cells but had no significant effect on ACR-induced PERK pathway activation; thus, PERK pathway-induced autophagy had an antiapoptotic role in this condition. This paper provides an experimental basis for exploring potential molecular targets to prevent and control ACR toxicity."

Journal

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. (PubMed, PLoS One) - "Previously, we showed that the PERK kinase inhibitor GSK2606414 delays cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. These results indicate that trazodone, DBM and TUDCA, at dosing regimens active in other neurodegenerative disease mouse models, have no disease-modifying effect in a preclinical model of MSS. This underscores the difficulty of translating neuroprotective strategies from other conditions to MSS, highlighting the need for more targeted therapeutic approaches."

Journal • Preclinical • Ataxia • CNS Disorders • Hepatology • Immunology • Movement Disorders • Sjogren's Syndrome • CALB1

Inhibition of SLC40A1 represses osteoblast formation via inducing iron accumulation and activating the PERK/ATF4/CHOP pathway mediated oxidative stress. (PubMed, Redox Rep) - "Similar trends were observed with respect to GSK2606414 treatment with siSLC40A1. SLC40A1 inhibition suppresses osteoblast formation by facilitating iron accumulation and activating the PERK/ATF4/CHOP pathway-mediated oxidative stress."

Journal • ATF4 • BMP2 • SLC40A1 • SPP1

Dysfunctional RNA binding protein induced neurodegeneration is attenuated by inhibition of the integrated stress response. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Small molecule inhibition of the ISR with either PERKi (GSK2606414) or ISRIB (integrated stress response inhibitor) attenuated both the decrease in neuronal translation and neurite loss, without affecting hnRNP A1 clustering. We then confirmed a strong association between hnRNP A1 clustering and ISR activation in neurons from MS brains. These data illustrate that hnRNP A1 dysfunction promotes neurodegeneration by activation of the ISR in vitro and in vivo, thus revealing a novel therapeutic target to reduce neurodegeneration and subsequent disability in MS."

Journal • Review • CNS Disorders • Multiple Sclerosis

Fucoidan alleviates hepatic lipid deposition by modulating the Perk-Eif2α-Atf4 axis via Sirt1 activation in Acanthopagrus schlegelii. (PubMed, Int J Biol Macromol) - "In the in vitro HFD model, GSK2606414 (GSK)-specific inhibition of the Perk pathway, decreased Pparγ nuclear translocation and increased Pparα nuclear translocation. Overall, fucoidan mitigated HFD-induced, Perk pathway-mediated lipid deposition in the liver of black seabream by activating Sirt1. The findings provided a new prospect for the application of green polysaccharides in aquatic animal feeds."

Journal • Hepatology • ATF4 • PPARA • PPARG • SIRT1

TREM1 induces microglial ferroptosis through the PERK pathway in diabetic-associated cognitive impairment. (PubMed, Exp Neurol) - "Moreover, PERK pathway of endoplasmic reticulum stress was activated by HG, and then reversed by PERK inhibitor GSK2606414 and LP17 followed by improved ferroptosis in HG-cultured BV2. In summary, our results indicated that TREM1 effectively aggravates T2DM-associated microglial iron accumulation through the PERK pathway of ERS, which contributes to antioxidant inactivation and lipid peroxidation, eventually, massively boosted ROS result in microglial ferroptosis. The mechanism elucidation in our study may shed light on targeted therapy of DACI."

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

Endoplasmic reticulum stress induces axon initial segment shortening via activation of the PERK pathway (Neuroscience 2024) - "Co-exposure to a PERK-specific inhibitor GSK2606414 (0.06 μM) prevented AIS shortening induced by TM. These results demonstrate ER stress is sufficient and necessary for AIS shortening in vitro. The PERK dependent nature of this AIS shortening supports the PERK pathway as a therapeutic target in T2DM related cognitive impairment."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Rotenone-induced cell apoptosis via endoplasmic reticulum stress and PERK-eIF2α-CHOP signalling pathways in TM3 cells. (PubMed, Ecotoxicol Environ Saf) - "Further intervention with the PERK inhibitor GSK2606414 reduced ROT-induced apoptosis and testosterone reduction by inhibiting PERK activity. In summary, ROT-induced male reproductive toxicity is specifically driven by apoptosis, with the PERK-eIF2α-CHOP signalling pathway activated by ER stress playing a crucial role in the apoptosis of Leydig cells triggered by ROT."

Journal

Dietary bitter ginger-derived zerumbone improved memory performance during aging through inhibition of the PERK/CHOP-dependent endoplasmic reticulum stress pathway. (PubMed, Food Funct) - "In contrast, GSK2606414 (a PERK inhibitor) significantly increased these effects of ZB. In summary, our results suggested that ZB prevented D-gal-induced cognitive deficits by blocking the PERK/CHOP-dependent ER stress pathway and apoptosis, suggesting that ZB might be a natural sesquiterpene molecule that relieves ARCD."

Journal • Alzheimer's Disease • Cognitive Disorders • HSPA5

Tetrahydrocurcumin Attenuates Polymyxin B Sulfate-Induced HK-2 Cells Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Mediated PERK/eIF2α/ATF4/CHOP Signaling Pathway Axis. (PubMed, Environ Toxicol) - "In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment."

Journal • ATF4

Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma. (PubMed, Neuro Oncol) - "We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ATF4 • BCL2L1 • CDKN1A • CXCL8 • ER • IL1B

Apigenin improves testosterone synthesis by regulating endoplasmic reticulum stress. (PubMed, Biomed Pharmacother) - "It was also observed that AP rescued testosterone synthesis enzymes in TM3 cells, similar to that observed with the inhibitor of the PERK pathway (GSK2606414)...Collectively, AP has remarkable potential to alleviate HFD-induced obesity and testicular dysfunction. Its protective effects are attributable partly to mitigating ERS and restoring testosterone synthesis in Leydig cells."

Journal • Genetic Disorders • Infertility • Metabolic Disorders • Obesity • Sexual Disorders • STAR

Intrinsic signaling pathways modulate targeted protein degradation. (PubMed, Nat Commun) - "The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors."

Journal • Oncology • Targeted Protein Degradation • BRD2 • BRD4 • CDC37 • CDK9 • TRIP12

Non-Canonical STING-PERK Pathway Modulation of Cellular Senescence and Therapeutic Response in Sepsis-Associated Acute Kidney Injury. (PubMed, Inflammation) - "The role of the STING-PERK pathway was investigated by silencing PERK in HK-2 cells and administering the PERK inhibitor GSK2606414...The STING-PERK signaling pathway exacerbates cell senescence and apoptosis in SA-AKI. Inhibiting this pathway could provide potential therapeutic targets for SA-AKI treatment."

Journal • Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • STING

Inhibition of ER Stress Using Tauroursodeoxycholic Acid Rescues Obesity-Evoked Cardiac Remodeling and Contractile Anomalies through Regulation of Ferroptosis. (PubMed, Chem Biol Interact) - "Moreover, in vitro results noted that TUDCA, PERK inhibitor GSK2606414, TFRC neutralizing antibody and ferroptosis inhibitor LIP1 mitigated palmitic acid-elicited changes in lipid peroxidation and mechanical function. Our findings favored a role for ferroptosis in obesity cardiomyopathy downstream of ER stress."

Journal • Cardiomyopathy • Cardiovascular • Genetic Disorders • Immunology • Obesity • ANXA2 • ATF4 • CDC37 • GPX4 • HSP90AA1 • HSPA5 • SLC7A11

Differential effects of montelukast and zafirlukast on MDA‑MB‑231 triple‑negative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress. (PubMed, Mol Med Rep) - "GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukast‑induced cell death. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATF6 • BCL2 • CASP3 • CASP7 • CCND1 • CDK4 • ERN1 • PCNA

Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway. (PubMed, Cell Death Discov) - "Additionally, SERCA-mediated ERS-induced apoptosis was attenuated by GSK2606414 treatment via inhibiting PERK-eIF2α-CHOP axis that not only curtailed the level of caspase-3 but also elevated the levels of PSD95 and SYN. These findings highlight the significant impact of heat stress on cognitive impairment, and further elucidate the underlying mechanism involving SERCA/PERK/eIF2α pathway."

Journal • Alzheimer's Disease • Cognitive Disorders • CASP3 • DLG4 • SYP

Elucidating PERK Mediated Cytokine Release During Influenza Infection (ATS 2024) - "Pro-inflammatory cytokines released under the control of PERK were identified using an inhibitor, GSK2606414 (PERKi) that inhibits PERK activation... These results suggest an important role for PERK in driving cytokine release during IAV infection while acting as a regulator for both UPR and ISR."

Infectious Disease • Influenza • Respiratory Diseases • CCL20 • IL6

Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress. (PubMed, Environ Pollut) - "Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC)...Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway."

Journal • Hepatology • Metabolic Disorders • ATF4 • HSPA5