GSK690693 / GSK - LARVOL DELTA

Kupffer cell M2-like polarization increases liver metastatic burden via the uptake of exosomal KRAS mutant protein from hypoxic colorectal carcinoma cells. (PubMed, RSC Med Chem) - "In vitro model HMDMs were used to explore polarization phenotype and therapeutic effects of GSK690693 (AKT inhibitor) inhibited AKT... our findings reveal that exosomal mutant KRAS drives Kupffer cell M2-like polarization via the hyperactivation of AKT signaling, establishing this axis as a key mediator of colorectal cancer liver metastasis. Pharmacological inhibition of AKT effectively disrupts this immunosuppressive reprogramming, proposing targeted AKT blockade as a promising strategy to intercept the metastatic niche in CRC patients."

Journal • Colorectal Cancer • Oncology • Solid Tumor • KRAS

A kinase inhibitor screen identifies GSK690693 as a Hippo pathway inhibitor targeting ER-positive breast cancer. (PubMed, J Biochem) - "These findings revealed a previously undefined mechanism of action of GSK690693 as a Hippo pathway inhibitor, underscoring its efficacy in mitigating ER-positive breast cancer progression. Given the broader implications of Hippo pathway dysregulation in multiple cancers, GSK690693 could be part of a combination regimen for various malignancies."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • LATS1

Small molecule splicing modulators that disrupt O-GlcNAc homeostasis. (PubMed, Nat Commun) - "Here we report the results of three parallel drug repurposing screens against the O-GlcNAc cycling enzymes in cells and in vitro that reveal kinase inhibitors GSK690693 and Y-33075 act as splicing modulators that disrupt O-GlcNAc homeostasis and simultaneously downregulate OGT and OGA. Evaluation of a panel of splicing modulators revealed three additional potent compounds (OTS964, indisulam, GNF2133) that similarly downregulate OGT and OGA with distinct splicing profiles. These findings reveal previously unobserved splicing modulator chemotypes and approaches to disrupt O-GlcNAc homeostasis."

Journal • OGA • OGT

Deficiency of METTL3 alleviates excessive autophagy and apoptosis in mice with slow transit constipation and glutamic acid-induced interstitial cells of Cajal via the activation of PI3K/AKT pathway. (PubMed, J Mol Histol) - "This study aims to investigate the effects of METTL3 on loperamide (LOP)-induced STC mice and glutamic acid-induced interstitial cells of Cajal (ICCs)...More importantly, the effect of METTL3 knockdown on proliferation and autophagy was significantly reversed in glutamic acid-induced ICCs treated with LY294002 or GSK690693. Mechanistically, METTL3 deletion exerts its STC-repressive influence through the activation of the PI3K/AKT pathway. Collectively, the findings indicate that METTL3 modulates PI3K/AKT-mediated autophagy following LOP and highlight the potential of METTL3 as a therapeutic target in STC treatment."

Journal • Preclinical • Constipation • Gastroenterology • Gastrointestinal Disorder • Pain • METTL3

Astragalus membranaceus injection activates mitophagy and protects mitochondrial function in chronic heart failure via inhibiting AKT/mTOR pathway. (PubMed, Sci Rep) - "Pharmacological activation of AKT/mTOR signaling using SC79 significantly suppressed mitophagic flux, whereas AMI treatment mirrored the effects of the AKT/mTOR inhibitor GSK-690693, effectively restoring mitophagy and mitochondrial homeostasis. AMI exerts its cardioprotective effects through inhibition of the AKT/mTOR pathway, thereby ameliorating maladaptive remodeling and mitochondrial dysfunction in CHF."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Metabolic Disorders

DPV UL46 activates EGFR-PI3K-AKT pathway to antagonize innate immunity by interfering with cGAS-STING-TBK-IRF7 Signalsome formation. (PubMed, Int J Biol Macromol) - "Treatment with inhibitors of EGFR (gefitinib), PI3K (LY294002), or AKT (GSK-690693) effectively blocked DPV-induced AKT1-Ser473 phosphorylation, weaken the inhibitory effect of DPV on cGAS+STING induced innate immunity and consequently suppressed viral replication in DEF cells. These findings provide the first evidence of a molecular mechanism by which DPV utilizes UL46 to hijack the EGFR-PI3K-AKT pathway, thereby interfering with the cGAS-STING-TBK1-IRF7 signalsome to evade host antiviral defenses. Our study provides novel mechanistic insights into DPV pathogenesis and identifies promising targets for antiviral intervention."

Journal • Infectious Disease • IFNB1 • IRF7 • STING

Endothelial cell-derived SDF-1α elicits stemness traits of glioblastoma via dual-regulation of GLI1. (PubMed, Theranostics) - "Preclinical studies indicated that the combination of the CXCR4 antagonist AMD3100 and the AKT inhibitor GSK690693 synergistically inhibits GBM cell progression. Our findings unveil a novel signaling axis between ECs and tumor cells that directly impacts the acquisition of stemness traits, suggesting that targeting this pathway could represent a promising therapeutic strategy against GBM."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • CXCL12 • GLI1

A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA). (PubMed, J Exp Med) - "Mutant embryos recapitulate key clinical features of KLA, including dilated lymphatics and pericardial edema, which are reversed by trametinib, a MEK inhibitor used in KLA treatment. Leveraging this model in combination with an AI-based high-throughput drug screening platform, we identify cabozantinib, a tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as promising candidates for treating KLA. Notably, both drugs normalized sprouting and migration of cultured LECs from a KLA patient. Overall, our novel zebrafish model provides a powerful platform to dissect KLA pathogenesis and identify new therapeutic avenues."

Journal • NRAS

Establishment of a patient-derived drug-resistant oral squamous cell carcinoma animal model. (PubMed, Animal Model Exp Med) - "At P2 (tumor volume: 40-80 mm3), mice received cisplatin (1 mg/kg, three times/week) with cetuximab (1 mg/kg, weekly), GSK690693 (10 mg/kg, five times/week), or rapamycin (4 mg/kg, five times/week). These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution, enabling the development of drug-resistant OSCC models. This study can offer methodological insights for precision therapy of OSCC."

Journal • Preclinical • Oncology • Oral Cancer • Squamous Cell Carcinoma • Transplantation

Identification of key modules and hub genes for sepsis-induced myopathy using weighted gene co-expression network analysis. (PubMed, Front Genet) - "Additionally, leveraging the Connectivity Map (CMAP) database allowed us to predict six potential pharmacological agents-halcinonide, lomitapide, TG-101348, GSK-690693, loteprednol, and indacaterol-that might serve as therapeutic interventions for SIM. This research advances our understanding of the molecular basis of SIM, presenting new diagnostic biomarkers and potential drug targets. Further studies with larger clinical datasets are warranted to validate these findings and explore the therapeutic potential of the identified drugs."

Journal • Infectious Disease • Inflammation • Myositis • Septic Shock • CXCL10 • IL6 • STAT1

Tea Polysaccharide Ameliorates Atherosclerosis by Inhibiting Insulin Resistance-Mediated Hepatic VLDL Overproduction. (PubMed, J Agric Food Chem) - "Moreover, the suppression effects of TPS3A on VLDL overproduction were synergistically strengthened by inhibitors targeting PI3K (Wortmannin), AKT (GSK690693), mTORC1 (Rapamycin), and FoxO1 (AS1842856). Overall, TPS3A holds promise in ameliorating AS by inhibiting hepatic VLDL overproduction through the IRS-mediated PI3K-AKT-mTORC1/FoxO1 insulin signaling pathways."

Journal • Atherosclerosis • Cardiovascular • ACACA • APOB • APOE • SORT1

Low-Dose Perifosine, a Phase II Phospholipid Akt Inhibitor, Selectively Sensitizes Drug-Resistant ABCB1-Overexpressing Cancer Cells. (PubMed, Biomol Ther (Seoul)) - "KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3...Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells...Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206)...These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells."

Journal • P2 data • Oncology • ABCB1

SGSM2 in Uveal Melanoma: Implications for Survival, Immune Infiltration, and Drug Sensitivity. (PubMed, Protein Pept Lett) - "SGSM2 may not only serve as an important indicator for prognostic assessment. Still, it may also be a key target for the development of new therapeutic approaches, providing new perspectives on the treatment of UVM patients."

Journal • Breast Cancer • Endocrine Cancer • Eye Cancer • Melanoma • Microsatellite Instability • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Uveal Melanoma • MSI

Design, synthesis and biological evaluation of a new series of imidazothiazole-hydrazone hybrids as dual EGFR and Akt inhibitors for NSCLC therapy. (PubMed, Eur J Med Chem) - "Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib...Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693...Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3

Stanniocalcin 2 promotes neuronal differentiation in neural stem/progenitor cells of the mouse subventricular zone through activation of AKT pathway. (PubMed, Stem Cells Dev) - "Notably, the neuronal differentiation induced by STC2 was blocked by AKT inhibitor GSK690693, while the AKT activator SC79 reversed the impact of STC2 knockdown on neuronal differentiation. Our findings indicate that enhancing STC2 expression in SVZ-derived NSPCs facilitates neuronal differentiation, with AKT regulation potentially serving as a key intracellular target of STC2 signaling."

Journal • Preclinical • STC • STC2

Resveratrol Delays Diabetic Cardiomyopathy Fibrosis by Regulating Mitochondrial Autophagy. (PubMed, Altern Ther Health Med) - "GSK690693 (an AMPK inhibitor) suppressed the expression of p-AMPK, SIRT1, and SIRT3 and enhanced the protein expression of p22, XBP1s, and PINK. Resveratrol postpones dilated cardiomyopathy fibrosis by regulating the mitochondrial autophagy response through the AMP-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog 1 (SIRT1)-mediated inositol-requiring enzyme 1 alpha (IRE1α)/PTEN-induced putative kinase 1 (PINK) signaling pathway."

IO biomarker • Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Immunology • BCL2 • ERN1 • SIRT1 • SIRT3 • XBP1

Integrated metabolomics and transcriptomics analyses reveal metabolic responses to TGEV infection in porcine intestinal epithelial cells. (PubMed, J Gen Virol) - "Exogenous addition of the AMPK activator COH-SR4 significantly downregulates stearoyl coenzyme A (SCD1) mRNA and inhibits TGEV replication; while exogenous GSK-690693 significantly promotes TGEV infection by inhibiting AMPK signalling pathway. In summary, our study provides insights into the key metabolites and regulators for TGEV infection from the metabolome and transcriptome perspective, which will offer promising antiviral metabolic and molecular targets and enrich the understanding of the existence of a similar mechanism in the host."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Novel Coronavirus Disease

LYC inhibits the AKT signaling pathway to activate autophagy and ameliorate TGFB-induced renal fibrosis. (PubMed, Autophagy) - "After intervention of cells with AAI and GSK-690693, the expression of PINK1, PRKN, MAP1LC3-II, BECN1, p-SMAD2 and p-SMAD3 was increased, and the expression of SQSTM1 was decreased. However, SC79 inhibited autophagy and reversed the inhibitory effect of LYC on EMT. The results showed that LYC could inhibit the AKT signaling pathway to activate mitophagy and reduce renal fibrosis.Abbreviation: AA: aristolochic acid; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB: actin beta; AKT/protein kinase B: thymoma viral proto-oncogene; BAF-A1: bafilomycin A; BECN1: beclin 1, autophagy related; CCN2/CTGF: cellular communication network factor 2; CDH1/E-Cadherin: cadherin 1; CKD: chronic kidney disease; COL1: collagen, type I; COL3: collagen, type III; CQ: chloroquine; ECM: extracellular matrix; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; LYC: lycopene; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MTOR:..."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Oncology • Renal Disease • Solid Tumor • Targeted Protein Degradation • Thymoma • Thymus Cancer • ACTA2 • BECN1 • CDH1 • CTGF • mTOR • NECTIN1 • PINK1 • PRKN • SMAD3 • SQSTM1 • TGFB1 • UBR5 • VIM

TRIM27 ameliorates ischemic stroke by regulating NLRP3 inflammasome-mediated pyroptosis via the Akt/Nrf2/HO-1 signaling. (PubMed, Exp Neurol) - "GSK690693 or ML385 treatment partially reversed the effect of TRIM27 overexpression in vitro. These findings indicate that TRIM27 overexpression ameliorates ischemic stroke by regulating NLRP3 inflammasome and Akt/Nrf2/HO-1 signaling. This study provides a novel target for treatment of ischemic stroke."

Journal • Cardiovascular • Ischemic stroke • Reperfusion Injury • NLRP3 • TRIM27

VEGF-A ameliorates ischemia hippocampal neural injury via regulating autophagy and Akt/CREB signaling in a rat model of chronic cerebral hypoperfusion. (PubMed, J Stroke Cerebrovasc Dis) - "Present results provide a novel neuroprotective effect of VEGF-A in CCH that is related to the inhibition of neuronal autophagy and activation of the Akt/CREB signaling, suggesting a potential therapeutic strategy for ischemic brain damage."

Journal • Preclinical • Cardiovascular • CNS Disorders • Vascular Neurology • BECN1 • CASP3

Regulatory role of PI3K/Akt/WNK1 signal pathway in mouse model of bone cancer pain. (PubMed, Sci Rep) - "When GSK690693, a new Akt inhibitor, was given and the absence of intermediate signal dominated by Akt is found, pain may be relieved by blocking the transmission of pain signal and raising the PWMT...Inhibition of Akt can reduce the levels of IL-17 and TNF-α, cut off the downstream WNK1 protein signal receiving pathway, increase the PWMT and relieve BCP in mice. To clarify the analgesic target of BCP, to provide reference and theoretical support for the clinical effective treatment of BCP and the development of new high-efficiency analgesics."

Journal • Preclinical • Breast Cancer • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor • IL17A • TNFA • WNK1

Identification of Tau-Tubulin Kinase 1 Inhibitors by Microfluidics-based Mobility Shift Assay from a Kinase Inhibitor Library. (PubMed, SLAS Discov) - "Among them, three compounds, AZD5363, A-674563 and GSK690693 inhibited hTTBK1 in an ATP competitive manner and molecular docking simulations revealed that they enter the ATP pocket and form one or two hydrogen bonds to the hinge region with hTTBK1. Another hit compound, piceatannol, showed non-ATP competitive inhibitory effect on hTTBK1 and may serve as a starting point to develop highly selective hTTBK1 inhibitors. Altogether, this study provided a new in vitro platform for the development of novel hTTBK1 inhibitors that might have potential applications in AD prevention."

Journal • Alzheimer's Disease • CNS Disorders

Sorafenib inhibits tumor-driven CAF invasion in head and neck squamous cell carcinoma (EACR 2023) - "Pharmacological Inhibition of the identified kinases were preformed using PD153035 (EGFR inhibitor), Sorafenib Tosylate (RAF1/BRAF inhibitor), SP600125 (MEKK4/MEKK7 inhibitor), GM6001 (MMP inhibitor) and GSK690693 (Akt inhibitor).Results and DiscussionsFunctionally, HNSCC-secreted factors specifically and robustly promoted fibroblast invasion, as well as MMP expression. Mechanistically, changes in phosphorylation patterns were identified upon treatment with HNSCC-derived CMs, and several kinases were identified to be hyperactive: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Among the pharmacological kinase inhibitors tested, RAF1/BRAF inhibitor Sorafenib was the most effective to block tumor-promoted fibroblast invasion.ConclusionHNSCC-secreted factors promoted invasion of stromal fibroblasts, which was robustly abolished by treatment with the RAF1/BRAF inhibitor Sorafenib, emerging as a rational approach to target the pro-invasive fibroblasts in the..."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AKT1 • ARAF • CAFs • MAP2K4 • MAP3K7 • RPS6KA3

AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis. (PubMed, Hematology) - "Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLX downregulation."

Journal • Hematological Malignancies • Leukemia • Oncology • BCL2L1

Apoptosis of pro-B lymphocytes induced by NR4A1 activation in the presence of gingival fibroblast exosomes and TNFα, caspase 8, STAT3, and Akt pathways modulators. (PubMed, Rom J Morphol Embryol) - "In order to experimentally evaluate the apoptosis of pro-B type lymphocytes, induced as a result of the known activation of orphan nuclear receptor 4A1 (NR4A1), through Cytosporone B (Csn-B, 10 μM), in the presence or absence of exosomes derived from gingival fibroblasts, we administered as a treatment: 1 μM R-7050 [functional inhibitor of tumor necrosis factor alpha (TNFα)], 1 μM Z-IETD-FMK (functional inhibitor of caspase 8), 1 μM GSK690693 (functional inhibitor of Akt 1∕2∕3 pathways) and, last but not least, 1 μM scutellarin [functional inhibitor of receptor activator of nuclear factor-kappa B ligand (RANKL)] and therefore of the signal transducer and activator of transcription 3 (STAT3) pathway. Firstly, it is really clear that the presence of exosomes in the pro-B lymphocytes culture medium amplified the apoptotic effects of 10 μM Csn-B. The inhibition of tumoral precursors development, namely the pro-B type, might be highly dependent on the inhibition of Akt 1∕2∕3..."

Journal • Oncology • CASP8 • NF-κβ • NR4A1 • TNFA