AZD1480 / AstraZeneca - LARVOL DELTA

Evaluation of the In Vivo Efficacy of the JAK Inhibitor AZD1480 in Uterine Leiomyomas Using a Patient-derived Xenograft Murine Model. (PubMed, Reprod Sci) - "These findings suggest JAK inhibition as a potential treatment for uterine leiomyomas by targeting angiogenesis. However, further studies are warranted to explore alternative JAK inhibitors, examine downstream effects, optimize dosing, and establish clinical efficacy and safety."

Journal • Preclinical • Oncology • Solid Tumor • Uterine Leiomyoma

Suppression of the JAK/STAT pathway inhibits neuroinflammation in the line 61-PFF mouse model of Parkinson's disease. (PubMed, J Neuroinflammation) - "AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • C1QA • CD74 • CD8 • IL1B • PTPRC • THY1

Zhiqiao Gancao decoction regulated JAK2/STAT3/ macrophage M1 polarization to ameliorate intervertebral disc degeneration. (PubMed, Heliyon) - "Primary macrophage M1 polarization was induced using LPS, with cells treated using the JAK2 inhibitor (AZD1480) and ZQGCD to evaluate macrophage polarization, cellular supernatant inflammatory factors, and JAK2/STAT3 pathway expression...There is macrophage infiltration in the intervertebral disc tissue of IDD rats, and JAK2/STAT3 pathway is activated, macrophages are polarized to M1 type, resulting in inflammatory microenvironment, leading to intervertebral disc degeneration and hyperalgesia. ZQGCD exhibited a delaying effect on IDD and improved hyperalgesia by inhibiting the JAK2/STAT3/macrophage M1 polarization pathway."

Journal • Pain • IL1B • IL6 • JAK2 • MMP3 • STAT3 • TNFA

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation. (PubMed, Biochem J) - "We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib,  Ipatasertib, LJ1308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a,  Temsirolimus and Tideglusib - each of which inhibits mTOR signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death."

IO biomarker • Journal

Oncostatin M promotes osteogenic differentiation of tendon-derived stem cells through the JAK2/STAT3 signalling pathway. (PubMed, J Orthop Surg Res) - "OSM promotes osteogenic differentiation of TDSCs and the JAK2/STAT3 signalling pathway plays an important role."

Journal

OTUB1 Promotes Glioblastoma Growth by Inhibiting the JAK2/STAT1 Signaling Pathway. (PubMed, J Cancer) - "In addition, we added the JAK2 inhibitor AZD1480 to explore the regulation of OTUB1 for JAK2/STAT1 pathway in GBM... Our study reveals a novel mechanism by which OTUB1 inhibits the JAK2/STAT1 signaling pathway. This contributes to a better understanding of OTUB1's role in GBM and provides a potential avenue for targeted therapeutic intervention."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • OTUB1

V-set and immunoglobulin domain containing 4 inhibits oxidative stress, mitochondrial dysfunction, and inflammation to attenuate Parkinson's disease progression by activating the JAK2/STAT3 pathway. (PubMed, J Neuroimmunol) - "VSIG4 suppresses oxidative stress, mitochondrial dysfunction, and inflammation by activating the JAK2/STAT3 pathway, which may be helpful in attenuating PD progression."

Journal • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Oncology • Parkinson's Disease • IL1B • TNFA

Suppression of the JAK/STAT Pathway Inhibits Neuroinflammation in the Mouse Model of Parkinson's Disease (IMMUNOLOGY 2024) - "AZD1480 treatment reduced cell numbers of the MG2, MM4, and T3 clusters and suppressed the expression of cluster-specific genes, including H2-Aa, H2-Ab1, Cd74, Tnf, Il1b, and C1qc in MM4 and T3. These results indicate that inhibiting the JAK/STAT pathway suppresses the infiltration and activation of specific macrophages and T-cells in our PD model."

Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CD74 • CD8 • IL1B • PTPRC • THY1

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy. (PubMed, Kidney Int Rep) - "JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction...In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN."

Journal • Preclinical • Glomerulonephritis • Hematological Malignancies • IgA Nephropathy • Leukemia • Obstructive Sleep Apnea • Oncology • Renal Disease • Respiratory Diseases • Sleep Disorder • LIF • LIFR • STAT1

M1 macrophage-derived oncostatin M induces osteogenic differentiation of ligamentum flavum cells through the JAK2/STAT3 pathway. (PubMed, JOR Spine) - "Upon knockdown of OSMR or GP130, or the addition of AZD1480 or Stattic, P-JAK2 and P-STAT3 expression were decreased and osteogenic differentiation was reduced. M1 Mφ-derived OSM induces osteogenic differentiation of LF cells and the JAK2/STAT3 signaling pathway plays an important role."

Journal • OSMR

High-dose radiation-resistant lung cancer cells stored many functional lipid drops through JAK2/p-STAT3/FASN pathway. (PubMed, J Cancer Res Clin Oncol) - "Our studies discovered that lipids deposited in HDRR-LCCs were due to endogenous de novo fatty acids synthesis and exogenous lipids uptake. JAK2/p-TAT3/FASN could be used as promising targets for radiotherapy sensitization. Our study provided a new theoretical basis for studying the mechanism of radiation resistance in lung cancer."

Journal • Lung Cancer • Metabolic Disorders • Oncology • Solid Tumor • FAS • FASN

Treatment Options for Hepatitis A and E: A Non-Systematic Review. (PubMed, Viruses) - "However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results."

Journal • Review • Autoimmune Hepatitis • Cholestasis • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure • HMOX1

Fu-Zheng-Tong-Luo formula promotes autophagy and alleviates idiopathic pulmonary fibrosis by controlling the Janus kinase 2/signal transducer and activator of transcription 3 pathway. (PubMed, J Ethnopharmacol) - "The FZTL formula can inhibit IPF injury and lung fibroblast activation. Its effects are mediated via the JAK2/STAT3 signaling pathway. The FZTL formula may be a potential complementary therapy for pulmonary fibrosis."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL6 • JAK2 • STAT3

JAK1/2 Inhibitor Suppresses Neuroinflammation in the Thy1 α-Syn Mouse Model of Parkinson’s Disease (P808) (IMMUNOLOGY 2023) - "AZD1480 treatment reduced the numbers of the pathogenic clusters, comparable to cell clusters in control monomer/PBS mice. Together, these results suggest inhibiting the JAK/STAT pathway suppresses the infiltration and activation of innate and adaptive cells, thereby reducing the neuroinflammatory response in the Thy1-PD model."

Late-breaking abstract • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CD19 • CD8 • PTPRC • THY1

JAK2/STAT SIGNALING: ROLE IN GENERATION OF INFLAMMATORY MESENCHYMAL CELLS IN ULCERATIVE COLITIS. (DDW 2023) - "This therapeutic improvement was comparable to the treatment with the JAK1/2 inhibitor AZD1480. Our data suggest that (1) JAK2/STAT3/5 signaling is critical to the activation of the pathological inflammatory responses inUC-MFs; and (2) inflammatory cytokines and LPS, both present in the UC colonic microenvironment are likely to contribute to the activation of JAK2/STATs in UC-MFs. Mesenchymal stromal cell-specific targeting of this pathway could be a potential avenue to overcome current challenges within UC-therapeutic approaches that use mesenchymal stem cells and pan-inhibitors of JAK/STATs."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CD4 • IFNG • IL15 • IL33 • IL6 • JAK3 • THY1 • TYK2

Ohwia caudata extract relieves the IL-17A-induced inflammatory response of synoviocytes through modulation of SOCS3 and JAK2/STAT3 activation. (PubMed, Environ Toxicol) - "Furthermore, AZD1480 (a JAK2-specific inhibitor) or WP1066 (a STAT3-specific inhibitor) affected the inflammatory mediators production in IL-17A-challenged synoviocytes, and OCE failed to mitigate the IL-17A-induced inflammatory mediators and SOCS3, acting as a feedback inhibitor of the JAK/STAT3 pathway, in the presence of SOCS3 siRNA, indicating that the beneficial effects of OCE on the regulation of inflammatory response homeostasis were dependent on SOCS3 and the JAK2/STAT3 signaling pathway. Our study also showed that SOCS3 was markedly activated by OCE in RA fibroblast-like synoviocytes, thereby decreasing the JAK/STAT3 pathway, and the IL-1β, and IL-6 activation. Thus, O. caudate should be further investigated as a candidate anti-inflammatory and anti-arthritic agent."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • IL17A • IL1B • IL6 • JAK2 • SOCS3 • STAT3

Countering antidrug antibodies to programmed cell death-1 blockade in mouse Pten-null prostate cancer (AACR 2023) - "Blocking STAT3 signaling with the JAK1/2 inhibitor AZD1480 restored PD-L1 blockade in pDCs and was associated with improved reduction of tumor burden...Our study shows that the presence of ADAs is associated with lack of antitumor responses to ant-PD-L1 blockade in a preclinical model of prostate cancer and provides additional data that will improve our understanding of ADAs against immune checkpoint inhibitors. This study also offers an approach to monitor ADA development and a platform to investigate novel approaches to target ADAs."

IO biomarker • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN • TP53

JAK inhibition as a therapeutic approach to enhance radiation response in rectal cancer (AACR 2023) - "In vitro, JAK inhibition with 10µM AZD1480 or Ruxolitinib significantly reduced viability of cell lines HCT116 (p=0.018) and SW620 (p=0.050). This study represented a step towards establishing the role of JAK inhibition as a therapeutic approach for RC. Ongoing research aims to validate the synergistic effect of combining JAK inhibition with radiation."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor • IL6 • JAK2

RATIONALE FOR THE USE OF PACRITINIB IN KSHV-MULTICENTRIC CASTLEMAN DISEASE (CROI 2023) - " JAK Inhibitors (ruxolitinib, AZD1480, baricitinib, peficitinib, and pacritinib) and other kinase inhibitors were purchased from commercial sources; pacritinib was also provided by CTI BioPharma. : Pacritinib inhibited cell growth in PEL lines. It also downregulated a number of cellular genes believed to be important for PEL growth and for KSHV-MCD pathogenesis. These effects may stem from its simultaneous inhibition of multiple kinases including JAK2, IRAK1, and FLT3."

Clinical • Hematological Malignancies • Kaposi Sarcoma • Lymphoma • Oncology • Rare Diseases • Sarcoma • Solid Tumor • FLT3 • IL6 • IRAK1 • JAK2

β2 Integrin-Dependent Adhesion Is Indispensable for Inflammatory HIF1α Activation in Human Neutrophils (KIDNEY WEEK 2022) - "Prolyl hydroxylases were inhibited with Roxadustat (ROX), and HIF1α translation with YC1. Signaling pathways were analyzed with β 2 -integrin antibodies and the JAK2 inhibitor AZD1480...Conclusion Human neutrophils are unable of activating HIF1α in suspension. In contrast, cytokine, β 2 -integrin, and prolyl hydroxylase co-operation at inflammatory sites enables strong HIF1α activation."

FN1 • HIF1A

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway. (PubMed, World J Emerg Med) - "These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy."

Biomarker • Journal • Tumor microenvironment • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CAFs • SOCS2

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer. (PubMed, J Pers Med) - "Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment."

Journal • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Immunology • Inflammation • Oncology • Solid Tumor • IL13 • IL4

Pan-Caspase Inhibitor zVAD Induces Necroptotic and Autophagic Cell Death in TLR3/4-Stimulated Macrophages. (PubMed, Mol Cells) - "Our data further support the involvement of autocrine IFNs action in reactive oxygen species (ROS)-dependent necroptosis, LPS/zVAD-elicited ROS production was inhibited by necrostatin-1, neutralizing antibody of IFN receptor (IFNR) and JAK inhibitor AZD1480. Accordingly, both cell death and ROS production induced by TLR ligands plus zVAD were abrogated in STAT1 knockout macrophages. We conclude that enhanced TRIF-RIP1-dependent autocrine action of IFNβ, rather than inhibition of ERK or Akt, is involved in TLRs/zVAD-induced autophagic and necroptotic cell death via the JAK/STAT1/ROS pathway."

IO biomarker • Journal • IFNAR2 • IFNB1 • RIPK1 • TLR3 • TLR4

Inhibition of the DOT1L/MPL/JAK2 Signaling Axis Selectively Targets TET2 Mutation-Driven Clonal Hematopoiesis (ASH 2021) - "Through this screen, we discovered that DOT1L inhibitors, including SGC0946 and pinometostat, preferentially reduced the competitive advantage of Tet2 -/- HPC HOXB4 cells...Given that Janus Kinase 2 (JAK2) is required to transduce signals downstream of the TPOR, we studied the effects of two potent JAK2 inhibitors, fedratinib and AZD1480, along with a JAK1/2 inhibitor, ruxolitinib, on Tet2 -/- and Tet2 +/+ HPC HOXB4 cells in competition assays...In summary, our data demonstrate that 1) the TPOR signaling pathway is upregulated in TET2 -mutated HSPCs through epigenetic dysregulation by DOT1L, and 2) inhibition of DOT1L or the MPL/JAK2 signaling axis selectively targets TET2 -mutated HSPCs. Our findings have important implications in the development of pharmacologic interventions against TET2 -mutation driven CHIP."

Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • DOT1L • MPL • TET2

Ivermectin accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation. (PubMed, Environ Toxicol) - "IVM accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • SQSTM1 • STAT3 • STAT5