GLG-302 / GLG Pharma - LARVOL DELTA

JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction. (PubMed, Mol Med) - "The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage."

Journal • Cardiovascular • Metabolic Disorders • HMGCS2 • IL6

Membrane Tension Gates AT2 Fate Selection by Regulating FGF Signaling (ATS 2025) - "DPs were treated with small molecules, to rise CMT (CHIR22901 and Methyl Beta cyclodextrin; MBCD), inhibiting either endocytosis (Dynasore) or pathways downstream of FGF signaling (FR180204, Akt VIII, KRpep-2d, NSC 74859)... We found that CMT reduces immediately prior to alveolar differentiation, and that increasing CMT with CHIR and MBCD blocks differentiation of DPs in culture. As CMT reduces, we observe an increase in endocytosis and internalization of Fgfr2 in both cultured cells and in vivo at E17.5. Further, scRNAseq analysis showed an upregulation of ERK target genes and we have validated higher ERK activity in nAT2s in the reporter line."

Respiratory Diseases • FGF • FGFR2

STAT3 Signaling Pathway in Health and Disease. (PubMed, MedComm (2020)) - "We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential."

Journal • Review • Cardiovascular • CNS Disorders • Immunology • Oncology • IL6

Diabetes Advances Cardiomyocyte Senescence Through Interfering Rnd3 Expression and Function. (PubMed, Aging Cell) - "The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • Targeted Protein Degradation

STAT3 AND LOW-DENSITY NEUTROPHILS MEDIATED T LYMPHOCYTE SUPPRESSION IN CERVICAL CANCER PATIENTS (IPVC 2024) - "To these cultures, we added or not, the STAT3 inhibitor NSC74859. Our RNA data showed enrichment of pathways and processes related to neutrophil migration and activation, we also found, among the enriched pathways, about 30% of genes that had a STAT3 binding element in their promoter region... Low-density neutrophils with a immunosuppressor phenotype are found in cervical cancer patients. These cells can inhibit T lymphocyte activation, through STAT3 signaling. Our data points to yet another immunosuppressive mechanism dependent on STAT3 and potential therapy target."

Clinical • IO biomarker • Cervical Cancer • Oncology • Solid Tumor • CD69 • CEACAM8 • ITGAM • PD-L1 • STAT3

Enhanced anti-tumor efficacy of S3I-201 in breast cancer mouse model through Wharton jelly- exosome. (PubMed, Cancer Cell Int) - "Our results demonstrate that WJ-Exo is an effective carrier for targeting S3I-201 to tumor cells and enhances the therapeutic efficacy of S3I-201 in tumor-bearing mice."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CASP3 • STAT3

Combining proteomics and Phosphoproteomics to investigate radiation-induced rectal fibrosis in rats and the effects of pSTAT3 inhibitor S3I-201 on human intestinal fibroblasts. (PubMed, J Proteomics) - "In our research, we utilized TMT labeling alongside LC-MS/MS techniques for an in-depth exploration of both proteomic and phosphoproteomic landscapes in rat models of radiation-induced intestinal fibrosis (RIRF). Our analysis shed light on the function and pathways of proteins and phosphorylated proteins triggered by radiation, as well as those offering protection against it. We mapped out a network of interactions within these proteins and validated the expression levels of key proteins through quantitative measures. Additionally, the study ventured into identifying STAT3 as a potential therapeutic target, evaluating the efficacy of the S3I-201 inhibitor in laboratory settings, and suggesting its utility for RIRF treatment. Overall, our findings provide groundbreaking insights into RIRF's underlying mechanisms, laying a solid foundation for developing future antifibrotic treatments."

Journal • Preclinical • Colorectal Cancer • Fibrosis • Gastrointestinal Cancer • Immunology • Oncology • Solid Tumor • CTGF • MYL9 • TGFB1

Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication. (PubMed, iScience) - "Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis."

Journal • Infectious Disease • Influenza • Respiratory Diseases • STAT3

Anti-tumor withanolides as signal transducers and activators of transcription 3 (STAT3)-inhibition from Withania obtusifolia. (PubMed, Fitoterapia) - "Of the isolated compounds, cytotoxicity of withanolide J, physaperuvin G, and a commercial STAT3 inhibitor (S3I-201) were assessed against a human leukemia HL-60 cell line resulting in IC50 values of 26, 29, and 120 μM, respectively. In silico molecular docking simulations indicate that withanolide J and physaperuvin G can bind as an inhibitor in the active site of STAT3 with docking scores comparable to the selective STAT3 inhibitor, S3I-201."

Journal • Hematological Malignancies • Leukemia • Oncology • STAT3

Methoxylated Flavones from Casimiroa edulis La Llave Suppress MMP9 Expression via Inhibition of the JAK/STAT3 Pathway and TNFα-Dependent Pathways. (PubMed, J Agric Food Chem) - "In addition, AG490 and S3I-201, inhibitors of Janus kinase (JAK) and STAT3, suppressed LPS-mediated MMP9 induction, suggesting that the casedulones suppressed MMP9 induction through the inhibition of JAK/STAT3 pathways...Moreover, tumor necrosis factor-α (TNFα)-mediated MMP9 induction was significantly suppressed in the presence of the casedulones. Taken together, these findings suggest that casedulones inhibit the IL-6/STAT3 and TNFα pathways, which all involve LPS-mediated MMP9 induction."

Journal • Oncology • IL6 • MMP9 • TNFA

IL-17A/IL-17RA interaction blockade sensitizes synovial macrophages to efferocytosis and PD-L1 signaling via rewiring STAT-3/ADAM17/MERTK axis in rheumatoid arthritis animal model. (PubMed, Int Immunopharmacol) - "Similar results were obtained in IL-17A-sensitized AA synovial macrophages treated with S3I-201 (a STAT-3 inhibitor) indicating that IL-17A influences efferocytosis via the STAT-3 pathway. In view of our previous work where cyanidin restored Th17/Treg balance, our present investigation fulfils a critical gap by providing scientific validation that cyanidin escalated PD-L1 expression during the efferocytosis process that could have impacted the restoration of Th17/Treg balance in an AA model. Together, these data corroborate the hypothesis that IL-17A signaling can impair efferocytosis via regulating STAT-3/ADAM17/FL-MERTK axis and that its inhibition can amplify a pro-resolution signal against RA progression."

IO biomarker • Journal • Preclinical • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • ADAM17 • CD163 • IL17A • IL17RA • MERTK • PD-L1 • STAT3 • STAT5

Diverse effect of STAT3 inhibition on murine primary tubular epithelial cells (ERA-EDTA 2024) - "We aimed to investigate in vitro the impact of pharmacological STAT3 inhibition with NSC74859 (NSC) and STATTIC on the expression of fibrosis associated genes of primary tubular epithelial cells... Our results indicate that in vitro inhibition of STAT3 using two inhibitors with same mode of action lead to diverse responses in primary murine tubular epithelial cells, partially suppressing EMT markers but inducing pro-fibrotic EGR2. Further studies are needed to clarify the underlying mechanisms."

Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • ACTA2 • COL1A1 • EGR2 • TGFB1

Inhibition of STAT3 by S3I-201 suppress peritoneal fibroblast phenotype conversion and alleviate peritoneal fibrosis. (PubMed, J Cell Mol Med) - "Blocking STAT3 can reduce the peritoneal morphological changes induced by chlorhexidine gluconate. In conclusion, our findings suggested STAT3 signalling played an important role in peritoneal fibrosis. Therefore, blocking STAT3 might become a potential treatment strategy in peritoneal fibrosis."

Journal • Fibrosis • Immunology • IL6 • STAT3

Expression analysis and mapping of Viral-Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox. (PubMed, BMC Infect Dis) - "MPXV circumvents cellular antiviral defenses by engaging histone modification and immune evasion strategies. C6R-derived protein K7 binding candidate molecule S3I-201 is a priority promising candidate for treating Mpox."

Journal • Infectious Disease

PLAU promotes cell proliferation and migration of head and neck cancer via STAT3 signaling pathway. (PubMed, Exp Cell Res) - "A recovery assay using S3I-201, a selective inhibitor of signal transducer and activator of transcription 3 (STAT3), indicated that PLAU promoted HNC cell line progression via STAT3 signaling in vitro...In summary, we identified the tumorigenic PLAU function in the HNC progress. PLAU may represent a potential prognostic biomarker of HNC and the PLAU-STAT3 pathway might be considered a therapeutic target of HNC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • PLAU • TNFRSF12A • TNFRSF25

The crosstalk between STAT3 and p53/ERK signaling regulates brain metastasis (AACR 2024) - "Human brain metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 inhibitor (NSC74859) or MAPK inhibitor (U0126) in regular or astrocytic media to determine cell proliferation and migration by MTT assay and scratch-wound, respectively...These findings suggest activation of STAT3 and ERK1/2 promote BM and suppression of these pathways may lead to a reduction in cell viability and motility. Therefore, this provides compelling evidence for the use of STAT3 and ERK1/2 along with p53 as potential targets for immunotherapy in brain metastatic disease."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • PD-L1 • STMN1 • TP53

PDP1 promotes the progression of breast cancer through STAT3 pathway. (PubMed, Cell Biochem Funct) - "Cell counting kit-8 assay showed that PDP1 overexpression significantly raised MDA-MB-231 and MCF7 cell viability while STAT3 inhibitor S3I-201 recovered the cell growth to normal level. To summarize, PDP1 promotes the progression of BC through STAT3 pathway by regulating p-STAT3. The findings contribute to understanding the molecular mechanisms underlying BC progression, and opening avenues for targeted therapeutic approaches."

Journal • Breast Cancer • Oncology • Solid Tumor • PDP1

Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets. (PubMed, Anticancer Res) - "Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM."

IO biomarker • Journal • Brain Cancer • Breast Cancer • Oncology • Solid Tumor • TP53

PCSK9 regulates myofibroblast transformation through the JAK2/STAT3 pathway to regulate fibrosis after myocardial infarction. (PubMed, Biochem Pharmacol) - "However, these effects were countered when co-incubated with the STAT3 inhibitor S3I-201. This study suggests that PCSK9 may function as a novel regulator of myocardial fibrosis, primarily via the JAK2/STAT3 pathway."

Journal • Cardiovascular • Dyslipidemia • Fibrosis • Immunology • Myocardial Infarction • PCSK9

Neuronal pyroptosis mediated by STAT3 in early brain injury after subarachnoid hemorrhage. (PubMed, Brain Res) - "After intracerebroventricular injection of STAT3 inhibitor S3I-201, they were divided into sham, SAH, SAH + Vehicle, and SAH + S3I-201...Our finding demonstrated that STAT3 regulates neuronal pyroptosis in EBI after SAH. Inhibition of STAT3 may be a potential target to attenuate the damage that triggers neuroinflammation after SAH."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • CASP1 • IL18 • IL1B • NLRP3 • STAT3

Melatonin attenuates cellular senescence and apoptosis in diabetic nephropathy by regulating STAT3 phosphorylation. (PubMed, Life Sci) - "We, for the first time, demonstrate that melatonin inhibits STAT3 phosphorylation, which is involved in alleviating the cellular senescence and apoptosis in DN."

Journal • Diabetes • Diabetic Nephropathy • Nephrology • Renal Disease • CASP9 • CDKN1A • IL6 • TP53

Pannexin 1 Modulates Angiogenic Activities of Human Endothelial Colony-Forming Cells Through IGF-1 Mechanism and Is a Marker of Senescence. (PubMed, Arterioscler Thromb Vasc Biol) - "Panx1 expression is upregulated in human ECFCs/EPCs with replication-induced senescence and during aging. Angiogenic potential of senescent ECFCs is improved by Panx1 reduction through increased IGF-1 production via activation of the FAK-ERK axis following calcium influx reduction. Our findings provide new strategies to evaluate EPC activities and rejuvenate senescent EPCs for therapeutic angiogenesis."

Journal • Cardiovascular • Oncology • CDKN2A • IGF1

The Role of STAT3 Signaling Pathway Activation in Subconjunctival Scar Formation after Glaucoma Filtration Surgery. (PubMed, Int J Mol Sci) - "Finally, S3I-201 treatment inhibited profibrotic gene expression and subconjunctival fibrosis in a rat model of GFS. In conclusion, our data suggests that STAT3 plays a central role in fibrosis induced by different profibrotic pathways and that STAT3 is a potential target for antifibrotic therapies following GFS."

Journal • Surgery • Fibrosis • Glaucoma • Immunology • Ophthalmology • IL6 • SOCS3 • TGFB1

The protective effect of leukemia inhibitory factor on apoptosis of BMSCs induced by hypoxia and serum-deprivation. (PubMed, Am J Transl Res) - "These data indicated that LIF played a protective role in apoptosis of BMSCs induced by ischemia via activating JAK1/STAT3 signaling pathway."

IO biomarker • Journal • Cardiovascular • Hematological Malignancies • Leukemia • Lymphoma • Oncology • ANXA5 • BCL2 • CASP3 • JAK1

Jing-Fang n-butanol extract and its isolated JFNE-C inhibit ferroptosis and inflammation in LPS induced RAW264.7 macrophages via STAT3/p53/SLC7A11 signaling pathway. (PubMed, J Ethnopharmacol) - "These results suggest that JFNE and JFNE-C may exert anti-inflammatory effect through activating the STAT3/p53/SLC7A11 signaling pathway to inhibit ferroptosis."

Journal • Inflammation • Oncology • GPX4 • IL1B • IL6 • SLC7A11 • TNFA