GW-2580 / GSK - LARVOL DELTA

Microglial Inhibition Promotes Proliferation and Differentiation of Neural Stem Cells via STAT3/SDF-1/CXCR4 Signaling Pathway in Hypoxic-Ischemic Encephalopathy. (PubMed, Glia) - "Finally, the inhibition or activation of STAT3 respectively decreased or increased the neuroprotective effects of GW2580 (p < 0.05-0.001). Collectively, our findings demonstrate that the STAT3 signaling pathway plays a critical role in the neuroprotective effects of microglial inhibition and may facilitate the development of novel therapeutic strategies to treat stroke."

Journal • Cardiovascular • CNS Disorders • CXCL12

Synergistic pharmacotherapy for epilepsy: NPY (3-36)-modified ZIF-90 nanoparticles co-delivering GW2580. (PubMed, Biomater Sci) - "NPY@ZIF-RG alleviated hippocampal neuronal loss and cognitive dysfunction by co-delivering GW2580 and NPY (3-36), which exerted synergistic neuroprotective and anti-inflammatory effects. This study provides a promising nanocomposite drug-delivery system for the treatment of epilepsy."

Journal • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation

Crystallized colony-stimulating factor-1 receptor inhibitor protects immunoisolated allo but not xeno transplants in primates. (PubMed, Sci Transl Med) - "Here, we demonstrate that coencapsulation of slow-releasing CSF1R inhibitor (GW2580) crystals with human stem cell-derived β cells (SC-β) in alginate spheres enables stable glycemic control for 1 year in immune-competent diabetic C57BL/6 mice...Chemokines CCL17, CCL22, and CXCL13 were among the most highly up-regulated transcripts, mirroring responses observed previously with profibrotic alginate formulations without cells. These findings underscore the issues associated with xenogeneic cell sources in higher-order species yet indicate that targeting innate immune pathways with localized CSF1R inhibition may be sufficient to enable function of encapsulated allogeneic cell therapies."

Journal • Transplantation • CCL2 • CCL22 • CD4 • CXCL13

Fluorine-18-labeled PET radiotracers for imaging the macrophage colony-stimulating factor 1 receptor (CSF1R). (PubMed, EJNMMI Radiopharm Chem) - "A series of new PET radiotracers for imaging CSF1R was synthesized and tested in vitro and in animals. One member of the series, 2-[18F]fluoro-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)pyrimidine-4-carboxamide ([18F]3), manifests PET imaging properties that may be suitable for further testing on non-human primate models of neuroinflammation and translation to human subjects."

Journal • Inflammation • CSF1R

M2 Macrophage-Derived TGF-β1 Drives Tendon Fibrosis in Rodent Tendinopathy Models. (PubMed, J Orthop Res) - "Pharmacological intervention was performed using GW2580 (CSF-1R antagonist), and genetic knockout experiments were conducted in a mouse model...Genetic deletion of Tgf-β1 in myeloid cells also alleviated fibrotic changes. In conclusion, M2 macrophage-derived TGF-β1 plays a crucial role in tendon fibrosis by activating the JNK signaling pathway, suggesting its potential as a therapeutic target."

Journal • Preclinical • Fibrosis • Immunology • MRC1 • TGFB1

CD44-mediated copper accumulation drives Ly6Chi macrophages activation in ulcerative colitis. (PubMed, Cell Signal) - "GW2580, which has been validated to effectively suppress the activation of Ly6Chi macrophages, ameliorated symptoms and pathological features in UC mice...The CD44 monoclonal antibody IM7 substantially reduced copper accumulation, restored ATP7A protein level, decreased ROS level, and suppressed inflammatory activation in Ly6Chi macrophages. These findings demonstrated that CD44-mediated copper accumulation drives the activation of Ly6Chi macrophages, representing a critical mechanism in the inflammatory pathogenesis of UC."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • ATP7A

The Role of Hematopoietic Stem Cells in Lung Cancer Response to Radiation Therapy (ASH 2023) - "Use of a therapeutic inhibitor of the CSF-1 receptor (GW2580) prevented HSPC differentiation in to M2-macrophages and significantly decreasing regrowth rates...Overall, these studies define a new understanding of tumor biology in which HSPCs are significant mediators of tumor response to RT. These findings also identify new cellular and molecular pathways to target in the treatment of NSCLC to achieve more optimal clinical outcomes."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CSF1R • ITGA6

Genomic Analysis Defines Increased Circulating, Monocyte-Derived Macrophages That Promote Immune Suppression in Mouse Models of FGFR1-Driven Leukemogenesis and Defines a Multigene Signature That Predicts AML Outcomes (ASH 2024) - "Importantly, treatment of leukemic mice with the CSF1R inhibitor GW2580, which suppresses macrophage function and reduces their viability, leads to improved survival accompanied by reduced levels of leukemia cells and increased T-cell levels...Overall, we demonstrate that a major part of the immune suppression in SCLL leukemia models involves suppression of T-cell function by circulating macrophages, and targeting macrophages in this system improves survival of mice engrafted with leukemia cells. In addition, we have also defined specific genetic reprogramming that is associated with the transition of monocytes into macrophages during leukemogenesis, potentially providing opportunities to target and reverse the immune suppressive microenvironment to improve AML outcome."

Genomic analysis • Omic analysis • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • FGFR1

Genomic Analysis Defines Increased Circulating, Leukemia-Induced Macrophages That Promote Immune Suppression in Mouse Models of FGFR1-Driven Leukemogenesis. (PubMed, Cells) - "Targeting these macrophages with the GW2580 CSF1R inhibitor leads to restored immune surveillance and improved survival. Overall, we demonstrate that circulating macrophages are responsible, at least in part, for the immune suppression in SCLL leukemia models, and targeting macrophages in this system improves the survival of leukemic mice."

Journal • Preclinical • Hematological Malignancies • Leukemia • Lymphoma • Oncology • FGFR1 • HSPA1A • NFKBIA

Development of a relapse-related RiskScore model to predict the drug sensitivity and prognosis for patients with ovarian cancer. (PubMed, PeerJ) - "Further, six drugs (Vinorelbine, GW-2580, S-Trityl-L-cysteine, BI-2536, CP466722, NSC-87877) were found to be correlated with the RiskScore. In addition, KRT19 silencing markedly inhibited the invasion and migration of OC cells. This study established a relapse-related RiskScore model based on five prognostic genes (LDHA, NOP58, NMU, KRT19, and RPS23), offering novel insights into the recurrence mechanisms in OC and contributing to the development of individualized treatment strategies."

Journal • Oncology • Ovarian Cancer • Solid Tumor • KRT19 • LDHA • NOP58 • RPS23

Evaluation of in vivo and in vitro binding property of a novel candidate PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, EJNMMI Radiopharm Chem) - "These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

Evaluation of in-vivo and in-vitro binding property of a novel PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, Res Sq) - "Addition of cold CPPC partially blocked in - vitro [ 11 C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Conclusions These results suggest [ 11 C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [ 11 C]CPPC and [ 11 C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer's disease. (PubMed, Aging (Albany NY)) - "Therefore, we evaluated in vitro and in silico activity of senolytics, dasatinib (1), nintedanib (2), fisetin (3), quercetin (4), GW2580 (5), and nootropic, meclofenoxate hydrochloride (6), toward AChE and BChE. Modeling studies showed 1-6 interacted with the same five binding locations of both ChEs, some of which may be allosteric sites. These agents may exert their beneficial effects, in part, by inhibiting ChEs associated with AD pathology and provide new avenues for development of next-generation inhibitors targeting pathology-associated ChEs."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Pharmacological Inhibition of Microglial Proliferation Supports Blood-Brain Barrier Integrity in Experimental Autoimmune Encephalomyelitis. (PubMed, Cells) - "Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • CSF1R

Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R. (PubMed, Glia) - "In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Inflammation • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • Psychiatry • Solid Tumor • CSF1R

Proguanil inhibits proliferation and migration in glioblastoma development through targeting CSF1R receptor. (PubMed, Cell Signal) - "More importantly, we found that Proguanil's inhibitory effect on U87MG cell growth and migration was positively correlated with CSF1R expression, and this effect diminished following CSF1R knockdown and Proguanil demonstrated synergistic effects with CSF1R-targeting positive drugs (BLZ945 and GW2580). Meanwhile, Proguanil targeted CSF1R to inhibit M2-type polarization of tumor-associated macrophages (TAMs) and their proliferation, thus altering the tumor microenvironment while indirectly suppressing the proliferation and migration of U87MG cells. Taken together, these findings suggest that Proguanil may serve as a promising CSF1R antagonist for GBM treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCND1 • CDK4 • CDKN1A • CSF1R • MAP2K1 • MMP3 • PTEN

CSF-1R blockade to alleviate azithromycin mediated immunosuppression in a mouse model of intracellular infection. (PubMed, Int Immunopharmacol) - "We further validated our results in Balb/c model of S. flexneri infection. Intrestingly, the CSF-1R blocker and azithromycin treated mice showed batter recovery than the azithromycin alone treated mice and hence we report the aftermath of GW2580 with azithromycin treatment on disease and immunological outcome of an intracellular infection caused by Shigella flexneri."

Journal • Preclinical • Immunology • Infectious Disease • AKT1 • CSF1R • STAT3 • STAT6

Bacterial nanocellulose as a simple and tailorable platform for controlled drug release. (PubMed, Int J Pharm) - "Inspired by the self-adhesion behavior of BNC upon drying, we proposed a BNC laminate entrapping commercial crystalline drugs (dexamethasone-DEX and GW2580) in a sandwich system. Mathematical modeling of the release data pointed to a diffusion-driven mechanism with non-fickian behavior. Overall, the results have demonstrated the potential of this simple approach for developing BNC-drug depots for localized and sustained release of therapeutic agents over adjustable timeframes."

Journal • Fibrosis • Immunology

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment. (PubMed, Sci Adv) - "Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses."

Journal • Gastroenterology • Inflammation

CSF1R MARKS A SUBSET OF FETAL LMPP WITH ACUTE MYELOID LEUKEMIA PROPAGATION PROPERTIES IN A MLL-AF9 MOUSE MODEL (EHA 2024) - " Doxycycline-inducible MLL-AF9+ mice were obtained from Juerg Schwaller's lab, and MLL-AF9 expression wasinduced from embryonic day (E) 12...Chemical inhibition of CSF1R (withGW2580) reduced the percentage of CD11b+ myeloid cells produced by CSF1R+ LMPPs at the end of theculture, compared with CSF1R+ LMPPs alone, which retained their mixed phenotype (B220+CD11b+)... Our data highlight the existence of a murine fetal population (CSF1R+ LMPPs) with leukemia-initiating cell andleukemic stem cell properties in the context of MLL-AF9+ AML. MLL-AF9+ CS1FR+ LMPPs share geneexpression patterns with HSC-like/LSC cells identified in pediatric patients, with LSC genes being highlyexpressed and OXPHOS downregulated. Functional validation of downstream signaling pathways of CSF1R is inprogress to understand their involvement in the observed lineage choices."

Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD79A • CDK1 • CSF1R • GATA2 • IKZF2 • ITGAM • KDM5B • MECOM • MEIS1 • MEN1 • MLLT3 • SOCS2 • SPN • TIMM13

Targeting the Lung - Brain Axis Improves Cigarette Smoke-induced Cognitive Outcomes (ATS 2024) - "CS exposure induced pulmonary impairments alongside recognition and spatial memory deficits like those seen in humans with COPD. A therapeutic treatment with the CSF1R antagonist, GW2580, partially restored the pulmonary inflammation by reducing the number of macrophage recruitment, and improved recognition and spatial memory. Future work will investigate if pharmacological modulation of CSF1R by GW2580 can resolve microglial hyperactivation."

Alzheimer's Disease • Chronic Obstructive Pulmonary Disease • CNS Disorders • Cognitive Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Identification of Selective Imidazopyridine CSF1R Inhibitors. (PubMed, ACS Med Chem Lett) - "Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat."

Journal • CNS Disorders • Oncology

Prognostic value and immunological role of MMRN1: a rising star in cancer. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "Drug sensitivity analysis found that MMRN1 was negatively correlated with several drugs, including GW-2580 and TL-1-85, suggesting that it can be used to develop potential anticancer therapies. Our analysis demonstrated a significant relationship between MMRN1 and prognosis, tumor immunity, and drug sensitivity of several tumors. As a rising star in cancer, it needs further research."

Journal • Oncology • Thrombosis • MMRN

Blocking Microglial Proliferation by CSF-1R Inhibitor Does Not Alter the Neuroprotective Effects of Adoptive Regulatory T Cells in 3xTg Alzheimer's Disease Mice. (PubMed, Curr Issues Mol Biol) - "In this study, we sought to determine whether adoptively transferred Tregs were effective when microglia proliferation was inhibited by using GW2580, which is an inhibitor of CSF1R...Our findings suggest that adoptively transferred Tregs can survive longer than 100 days in the brain, suppressing microglial activation and thus alleviating AD pathology. The present study provides valuable evidence to support the prolonged efficacy of adoptive Treg therapy in AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation

CSF1R blockade slows progression of cerebral hemorrhage by reducing microglial proliferation and increasing infiltration of CD8 + CD122+ T cells into the brain. (PubMed, Int Immunopharmacol) - "Using a colony-stimulating factor-1 receptor antagonist (GW2580), we observed that inhibition of microglia proliferation significantly ameliorated neurobehavioral deficits, attenuated cerebral edema, and reduced hematoma volume after ICH...Thus, inhibition of microglial proliferation offers a new perspective for clinical translation. The cross-talk between multiple cells involved in the regulation of the inflammatory response highlights the comprehensive nature of neuroimmunomodulation."

Journal • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Vascular Neurology • CD8 • CSF1R • CXCL10 • CXCR3 • IL10