WP1066 / Moleculin, WPD Pharma - LARVOL DELTA

Melatonin Promotes Neurogenesis via the JAK2/STAT3 Pathway in Hypoxic-Ischemic Neonatal Rats. (PubMed, Neurochem Res) - "In addition, the use of a JAK2 inhibitor (WP1066) and agonist (C-A1) verified that Mel exerted its protective effects by down-regulating the JAK2/STAT3 pathway. Morris water maze further confirmed that Mel improved spatial learning and memory function in neonatal rats with HIBD. Multimodal MRI offers a visual basis for monitoring metabolic changes and therapeutic effects, while Mel enhances neurogenesis and mitigates brain injury through inhibition of the JAK2/STAT3 pathway, thus providing a theoretical basis for the clinical application of Mel in HIBD in neonates."

Journal • Preclinical • CNS Disorders • Metabolic Disorders • Solid Tumor • Vascular Neurology • NES

Apelin-13 attenuates microglia-mediated neuroinflammation following intracerebral hemorrhage via targeting JAK2/STAT3 signaling pathway. (PubMed, Exp Neurol) - "Apelin-13 attenuated brain injury after ICH by suppressing microglia-mediated neuroinflammation through APJ receptor-dependent inhibition of the JAK2/STAT3 pathway."

Journal • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • Vascular Neurology

WP1066 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: Northwestern University | Active, not recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IDH1 • MGMT

Moleculin Announces Positive Results from Phase 1 Clinical Trial Evaluating WP1066 for the Treatment of Pediatric Recurrent Malignant Brain Tumors (Moleculin Press Release) - "For the Phase 1 trial, 10 children were treated with WP1066 twice daily for 14 days to determine the maximum feasible dose. Compassionate use treatment in three children with high-grade glioma was also evaluated. Results showed there was no significant toxicity, and a maximum feasible dose was determined. Importantly, WP1066 suppressed the expression of STAT3, inhibiting its activity and demonstrating anti-tumor immune responses."

P1 data • Glioma

Amphiphilic Polymeric Micelle Spherical Nucleic Acids (SNAs) as Drug Delivery Vehicles. (PubMed, Bioconjug Chem) - "Oligonucleotide sequence influences the extent of cellular uptake in Caki-1 cells; T20-SNAs exhibit ∼40% greater uptake compared to CpG and G-quadruplex sequences after 24 h. These structure-dependent properties lead to a 40% improvement in WP1066 potency when delivered via T20 benzyl APM-SNAs, reducing the drug's EC50 from 6.18 to 3.54 μM. Collectively, these results demonstrate that increasing the hydrophobicity of the APM-SNA core and the interactions between the core and the drug enhance drug encapsulation efficiency, prolong release kinetics, and improve therapeutic efficacy."

Journal

Soluble E-cadherin-STAT3/NFκB axis in inflammatory breast cancer progression (SABCS 2025) - "Pharmacological inhibition studies with STAT3 and NFκB pathway inhibitors (WP1066 and ATL) were conducted to evaluate pathway dependencies... Our findings demonstrate that sEcad is a key driver of aggressive oncogenic features in IBC through PDIA4-dependent activation of STAT3 and NFκB pathways. Targeting the sEcad-STAT3/NFκB signaling axis represents a promising therapeutic strategy for IBC."

Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • CDH1 • PDIA4 • STAT3

First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients. (PubMed, JCI Insight) - P1 | "WP1066 is safe, has minimal toxicity, and induces anti-tumor immune responses in pediatric brain tumor patients. Phase II investigation of WP1066 at the MFD in this patient population is warranted."

Journal • P1 data • Brain Cancer • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • CD4 • CD8 • STAT3 • TNFA

Jolkinolide B Mitigates Cerebral Ischemia-Reperfusion Injury by Promoting Microglial M1/M2 Polarization Through the JAK2/STAT3 Signaling Pathway. (PubMed, CNS Neurosci Ther) - "The ability of JB to modulate microglial polarization through JAK2/STAT3 inhibition presents a promising pharmacological approach for cerebral ischemia-reperfusion injury management in stroke therapy."

Journal • Cardiovascular • Inflammation • Ischemic stroke • Reperfusion Injury • IFNG • IL1B • MRC1 • TNFA

Allicin reduces airway inflammation and remodeling in a murine asthmatic model. (PubMed, Biochem Biophys Res Commun) - "The STAT3 agonist Colivelin reverses the anti-proliferative effects of allicin, while the inhibitor WP1066 enhances these effects. These findings collectively suggest that allicin exerts its anti-inflammatory and anti-remodeling effects in asthma by targeting the STAT3/PIM1 pathway, providing a new therapeutic strategy for asthma treatment."

Journal • Preclinical • Asthma • Immunology • Inflammation • Oncology • Pulmonary Disease • Respiratory Diseases • IL13 • IL4 • IL5 • PIM1 • TGFB1

Research on the potential mechanisms and therapeutic drug for the co-occurrence of major depressive disorder in castration-resistant prostate cancer. (PubMed, Sci Rep) - "The study further suggested that the JAK/STAT inhibitor WP1066 may be a potential drug for treating CRPC/MDD comorbidity, and this was validated through molecular docking. These findings not only provide a new perspective on the relationship between CRPC and MDD but also offer important clues for the development of treatment strategies."

Journal • Castration-Resistant Prostate Cancer • CNS Disorders • Depression • Genito-urinary Cancer • Major Depressive Disorder • Mood Disorders • Oncology • Prostate Cancer • Psychiatry • Solid Tumor

SPP1+ macrophages promote colorectal cancer progression by activating JAK2/STAT3 signaling pathway. (PubMed, Sci Rep) - "In contrast, after the cells were co-treated with WP1066 on the basis of co-culture with SPP1+ TAMs, MC38 cell viability was decreased, and apoptosis was increased; the levels of JAK2, STAT3, and their phosphorylation were decreased, and the EMT process was inhibited. Therefore, SPP1+ TAMs promote CRC cell proliferation and EMT by activating JAK2/STAT3 signaling pathway."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CXCL9 • SPP1

Matrine alleviates the immune imbalance of atopic dermatitis by up-regulating FOXO4 to inactivate circTNFRSF21-mediated JAK/STAT3 axis. (PubMed, Immunopharmacol Immunotoxicol) - "WP1066 (JAK/STAT3 inhibitor) eliminated the role of circTNFRASF21 overexpression in MT treated HaCat cells. MT alleviates the inflammatory response of atopic dermatitis by suppressing circTNFRSF21 expression to decrease the activity of STAT3 signaling pathway."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • ELAVL1 • IFNG • TNFA • TNFRSF21

WP1066 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: Northwestern University | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IDH1 • MGMT

Characterization of radiation electrophysiological properties of U87 cells induced by ionizing radiation and STAT3 inhibitors under microelectrode matrix sensor. (PubMed, Brain Res Bull) - "This novel study establishes a practical and theoretical foundation for radiation electrophysiology research by demonstrating that the cellular impedance-sensing system based on microelectrode arrays can detect ionizing radiation-induced and drug-induced glioblastoma cell death in real-time."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • CASP3

STAT3 inhibition in combination with CD47 blockade inhibits osteosarcoma lung metastasis. (PubMed, Front Immunol) - "Here we investigated the therapeutic activity of the orally bioavailable STAT3 inhibitor, WP1066, and anti-CD47 antibody using OS mouse models...This was associated with increased frequency of activated CD8+ T cells, NK cells and macrophages in the lungs and LDLNs. Our preclinical studies support further investigation of targeting STAT3 and CD47 as novel immunotherapeutic approach against OS lung metastasis."

IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8 • CD80

Role of the CEACAM7-JAK2/STAT3-BST2 Axis in the migration of nasopharyngeal carcinoma cells. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "These findings indicate that the CEACAM7/JAK2/STAT3/BST2 axis plays a crucial role in promoting NPC cell migration and underscore its potential as a therapeutic target for mitigating NPC metastasis."

Journal • Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • BST2 • CEACAM5 • JAK2 • STAT3

PSME2 promotes malignant progression through autophagy modulation via IL-6/STAT3 signaling pathway in esophageal squamous cell carcinoma. (PubMed, Life Sci) - "The study shows the promising role of PSME2 as a therapeutic target in ESCC management. The combined inhibition of PSME2 and activated pathways ensures effective suppression of tumor growth and proliferation, thus offering a novel strategy for better treatment outcomes in ESCC patients."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • IL6 • PSME2

A pH-Sensitive Nanosized Covalent-Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition. (PubMed, Adv Sci (Weinh)) - "The signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 is further encapsulated into COPs to form a WP1066-loaded COP (TVW)...The antitumor capacity of photodynamic immunotherapy is extensively investigated in a murine subcutaneous hepatocellular carcinoma model. This photo-immunotherapy may provide an effective combination regimen for the efficient treatment of solid tumors such as hepatocellular carcinoma."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • STAT3

WP1066 & Brain Tumors (GlobeNewswire) - "Also, the Company has signed an agreement with Emory University enabling Emory to study various WP1066 IV formulations in preclinical studies with the goal of selecting the best molecule to move into a clinical setting towards, most likely, brain cancers such as GBM. Study drug was delivered in April 2025 to Emory with results from such studies expected in the second half of 2025."

Licensing / partnership • Preclinical • Glioblastoma

STAT3 induces amygdala apoptosis by regulating the expression of stathmin in the rat model of posttraumatic stress disorder. (PubMed, Folia Neuropathol) - "In addition, following the administration of the STAT3 inhibitor, WP1066, there was a notable reduction in the apoptosis rate, leading to decreased levels of fear and anxiety in rats exposed to SPS...The findings above suggest that SPS could potentially modulate the stathmin gene's expression by activating the STAT3 pathway, subsequently leading to apoptosis in amygdala cells. This sequence of events ultimately contributes to the PTSD rat model fear memory impairment."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • STAT3

Molecular mechanisms underlying TXNIP's anti-tumor role in breast cancer, including interaction with a novel, pro-tumor partner: CAST. (PubMed, Cell Death Dis) - "Finally, cells with high levels of TXNIP expression displayed increased susceptibility to IL-24 and WP1066, a specific STAT3 inhibitor, suggesting possible predictive value for TXNIP. Collectively, these findings unveil novel TXNIP-dependent pathways that may contribute to breast cancer pathogenesis, enriching our understanding of this molecule's intricate role in cancer and potentially paving the way for clinical translation."

Journal • Breast Cancer • Oncology • Solid Tumor • CAST • TXNIP

CXCR4 confers stemness and radioresistance in chordoma cells. (PubMed, Cancer Biol Ther) - "Knockdown of CXCR4 expression using short hairpin RNA, inhibition of CXCR4 signaling with AMD3100, and targeting of STAT3, a downstream effector of CXCR4, with WP1066 in DTC cells significantly diminished their self-renewal ability, tumorigenic potential, IR resistance, and Sox2 expression. Furthermore, DTC cells infected with shCXCR4 exhibited substantial tumor suppression, and the combination of IR and AMD3100 significantly reduced DTC tumor growth in a mouse xenograft model. These findings underscore the functional significance of CXCR4 as a CSC marker, highlighting its potential as a therapeutic target for malignant chordomas."

Journal • Chordoma • Oncology • CXCR4 • SOX2 • STAT3

Network pharmacology integrated with experimental validation reveals the mechanism of Xanthii Fructus against allergic rhinitis via JAK2/STAT3/HIF-1α signaling pathway. (PubMed, J Ethnopharmacol) - "The combined findings led to the conclusion that XF play its therapeutic role in AR by suppressing the JAK2/STAT3/HIF-1α signaling pathway."

Journal • Allergic Rhinitis • Immunology • Inflammation • CCL11 • HIF1A • IL1B • IL4 • IL6 • MT-CO2 • TLR4 • TNFA • TSLP

Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway. (PubMed, PLoS One) - "Conversely, JAK2/STAT3 inhibitor WP1066 had markedly reduced p-JAK2 and p-STAT3 protein levels in IL6ST overexpression group. Inhibiting JAK2/STAT3 signaling pathway had mitigating effect on proliferative and invasive enhancement of endometrial stromal cells, as well as inhibition of apoptosis induced by IL6ST. These findings offer novel potential targets and strategies for the treatment of endometriosis."

Journal • Endometriosis • Gynecology • Inflammation • Women's Health • HIF1A • IL6ST • MAPK9

Stem cell factor restrains endoplasmic reticulum stress-associated apoptosis through c-Kit receptor activation of JAK2/STAT3 axis in hippocampal neuronal cells. (PubMed, PLoS One) - "We found that SCF inhibits L-Glu-induced ER stress-associated apoptosis via JAK2/STAT3 axis in HT22 hippocampal neuronal cells, as well as in primary hippocampal neurons from APP/PS1 mice, which provides valuable insights into the molecular mechanisms underlying the pathogenesis of AD and explores novel therapeutic targets for both sporadic and familial AD."

Journal • Alzheimer's Disease • CNS Disorders • Geriatric Disorders • CASP3 • HSPA5 • JAK2 • KIT