- |||||||||| GW-2580 / GSK, PLX5622 / Daiichi Sankyo, Turalio (pexidartinib) / Daiichi Sankyo
Review, Journal: Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of (Pubmed Central) - Feb 22, 2025
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.
- |||||||||| GW-2580 / GSK, TL-1-85 / Massachusetts General Hospital, Wellcome Sanger Institute
Journal: Prognostic value and immunological role of MMRN1: a rising star in cancer. (Pubmed Central) - Jan 8, 2025
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.
- |||||||||| dexamethasone / Generic mfg., GW-2580 / GSK
Journal: Bacterial nanocellulose as a simple and tailorable platform for controlled drug release. (Pubmed Central) - Sep 1, 2024
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.
- |||||||||| GW-2580 / GSK
Journal: Identification of Selective Imidazopyridine CSF1R Inhibitors. (Pubmed Central) - May 15, 2024
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.
- |||||||||| GW-2580 / GSK
Journal: CSF1R blockade slows progression of cerebral hemorrhage by reducing microglial proliferation and increasing infiltration of CD8 (Pubmed Central) - May 11, 2024
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.
- |||||||||| GW-2580 / GSK
Targeting the Lung - Brain Axis Improves Cigarette Smoke-induced Cognitive Outcomes (San Diego Convention Center, Area F (Hall A-B2, Ground Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_4199;
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.
- |||||||||| GW-2580 / GSK
Journal: Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment. (Pubmed Central) - Dec 17, 2023
Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented...Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
- |||||||||| GW-2580 / GSK
The Role of Hematopoietic Stem Cells in Lung Cancer Response to Radiation Therapy (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_1712;
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.
- |||||||||| GW-2580 / GSK
Journal: CSF1R inhibition at chronic stage after spinal cord injury modulates microglia proliferation. (Pubmed Central) - Aug 4, 2023
Together our study shows that there is a persistent microglia proliferation induced by SCI and that a pharmacological treatment at chronic stage after SCI modulates microglial responses. Thus, a transient oral GW2580-delivery at chronic stage after injury may provide a promising therapeutic strategy for chronic SCI patients.
- |||||||||| GW-2580 / GSK
CSF-1R SYSTEM ACTIVATES PARIETAL EPITHELIAL CELLS LEADING TO FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) (Focussed Oral Room 9) - May 4, 2023 - Abstract #ERAEDTA2023ERA_EDTA_1813;
To this end, we treated or not ADR-animals with CSF-1R specific inhibitors, GW2580 or Ki20227 (n=5-7 group)... In this study we propose a novel therapeutic strategy to FSGS-associated pathology based on the inhibition of CSF1-R activity having an impact on reducing aPECs, glomerulosclerosis, proteinuria, improving renal function and preserving the podocyte-progenitor phenotype, thus, in podocyte preservation against damage.
- |||||||||| GW-2580 / GSK
Journal: Intraocular delivery of ZIF-90-RhB-GW2580 nanoparticles prevents the progression of photoreceptor degeneration. (Pubmed Central) - Feb 8, 2023
Following the intraocular delivery of ZIF-90-RhB-GW2580 nanoparticles, the microglial proliferation and inflammatory response were significantly inhibited; moreover, the photoreceptors underwent alleviated injury with a recovery of retinal structure and visual function. In conclusion, the intraocular injection of ZIF-90-RhB-GW2580 at the early stage enables the precise delivery and sustained release of the GW2580, thus preventing the progression of photoreceptor degeneration.
- |||||||||| GW-2580 / GSK, sotuletinib (BLZ-945) / Novartis, BMS, Turalio (pexidartinib) / Daiichi Sankyo
Reprogramming of microglia/macrophages in glioblastoma improves anti-tumor T cell responses (West/Central Hall) - Sep 28, 2022 - Abstract #SNO2022SNO_734;
Finally, treatment of patient-derived GAMs led to an increased T cell transmigration through a dense barrier of autologous tumor-derived endothelial cells and increased the ability of T cells to kill autologous tumor cells. Our results support CSF1R blockade is able to reduce the immunosuppressive and pro-tumorigenic functions of GAM substantially and thereby could enhance the effectiveness of T cell-based immunotherapy.
- |||||||||| GW-2580 / GSK
Journal: Regulated macrophage immune microenvironment in 3D printed scaffolds for bone tumor postoperative treatment. (Pubmed Central) - May 17, 2022
In this study, a regenerative scaffold regulating the macrophage immune microenvironment and promoting bone regeneration in a dual-stage process for the postoperative treatment of bone tumors was constructed by binding a colony-stimulating factor 1 receptor (CSF-1R) inhibitor GW2580 onto in situ cosslinked hydroxybutylchitosan (HBC)/oxidized chondroitin sulfate (OCS) hydrogel layer covering a 3D printed calcium phosphate scaffold based on electrostatic interaction...At the later stage of treatment, calcium phosphate component of the scaffold can facilitate the repair of bone defects caused by tumor excision. In conclusion, the difunctional 3D printed bone repair scaffold regulating immune microenvironment in stages proposed a novel approach for bone tumor postoperative treatment.
- |||||||||| GW-2580 / GSK
ELUCIDATION OF MUTANT P53-MEDIATED MECHANISMS IN PROMOTING METASTATIC ESOPHAGEAL CANCER (ePoster - DDW Virtual) - Apr 25, 2022 - Abstract #DDW2022DDW_1498;
Conclusion : We have demonstrated novel roles and mechanisms of mutant p53-dependent CSF1/CSF1R autocrine signaling and its mediators in promoting lung metastasis from ESCC that may be applicable to other squamous cell cancers. We believe targeting this mechanism can open new therapeutic avenues.
- |||||||||| GW-2580 / GSK
The protective effects of CSF-1R inhibition on bladder outlet obstruction (BOO) induced remodeling (Room 244) - Apr 10, 2022 - Abstract #AUA2022AUA_1684;
Pro-fibrotic F4/80+aSMA+ macrophage to myofibroblast transition and CD163+TGF-ß1+ cells were also statistically significant decreased in GW2580 group when compared to vehicle group. Conclusions : In summary, our findings supported that targeting macrophage through inhibiting CSF-1R signaling might be a promising strategy for the treatment of BOO-induced remodeling.
- |||||||||| GW-2580 / GSK
Preclinical, Journal: Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates. (Pubmed Central) - Feb 5, 2022
Finally, GW2580-treatment in mice induced down-regulation of proliferation-associated transcripts and inflammatory associated genes in microglia that may account for reduced neuroinflammation and improved functional recovery following SCI. Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.
- |||||||||| GW-2580 / GSK
Preclinical, Journal, Head-to-Head: PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. (Pubmed Central) - Nov 21, 2021
unlabeled tracer) treatment reduced the uptake of C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-CPPC. In summary, our results demonstrated that C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
- |||||||||| GW-2580 / GSK
Preclinical, Journal: Efficient radiosynthesis and preclinical evaluation of [ F]FOMPyD as a PET tracer candidate for TrkB/C receptor imaging. (Pubmed Central) - Sep 22, 2021
Herein we report an efficient radiolabeling of a F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R)...The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [ F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.
- |||||||||| GW-2580 / GSK
Clinical, Journal: Early life stress exposure worsens adult remote microglia activation, neuronal death, and functional recovery after focal brain injury. (Pubmed Central) - May 28, 2021
Notably, prevention of microglia/macrophages activation by GW2580 treatment during ELS exposure significantly reduced microglia responses, cell death and improved functional recovery...Our findings highlight that ELS impacts the immune system maturation producing permanent changes, and that it is a relevant factor modulating the response to a CNS damage. Further studies are needed to clarify the mechanisms underlying the interaction between ELS and brain injury with the aim of developing targeted treatments to improve functional recovery after CNS damage.
- |||||||||| GW-2580 / GSK
Journal: Selective Loss of Brain-Derived Neurotrophic Factor Exacerbates Brain Injury by Enhancing Neuroinflammation in Experimental Streptococcus pneumoniae Meningitis. (Pubmed Central) - Apr 7, 2021
To investigate the role of microglia/macrophage in infected BDNF conditional knockout mice, GW2580 was used for microglia/macrophage depletion...Furthermore, targeted depletion of microglia/macrophage population decreased the resistance of mice to PM with diminishing neuroinflammation in BDNF conditional knockouts. Our findings suggest that loss of BDNF may enhance the inflammatory response and contribute to brain injury during PM at least partially by modulating TLR2- and NOD2-mediated signaling pathways, thereby providing a potential therapeutic target for future interventions in bacterial meningitis pathologies.
- |||||||||| GW-2580 / GSK, BLZ-945 / Novartis, BMS
Journal: CSF1R is required for differentiation and migration of Langerhans cells and Langerhans cell histiocytosis. (Pubmed Central) - Jan 6, 2021
We also detected presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF-1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAFV600E and wild-type forms of the disease.
- |||||||||| methotrexate / Generic mfg.
Journal: Targeting colony stimulating factor-1 receptor signalling to treat ectopic pregnancy. (Pubmed Central) - Dec 22, 2020
A single, systemic dose of methotrexate, a DNA-synthesis (S phase) inhibitor, has been used since 1991 for outpatient treatment of women with stable EP...We show that a specific CSF-1R kinase inhibitor, GW2580, abolishes CSF-1 induced trophoblast cell proliferation and migration and can be cytotoxic...Our data suggests that CSF-1 is involved in the survival and proliferation of trophoblast cells in EP. This suggests that pharmacological disruption of CSF-1/CSF-1R signaling axis could be the basis of a new therapeutic for EP.
- |||||||||| GW-2580 / GSK
[VIRTUAL] Tumor mhicroenvironment effects on hematopoietic stem cell induced tumor growth following radiation therapy (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1194;
In addition, we show that inhibition of CSF-1R phosphorylation using a pharmacologic inhibitor (GW2580) had no effect on HSPCs numbers but resulted in significantly decreased M2 macrophage numbers resulting in decreased tumor growth and regrowth (p<0.005)...Interestingly, Laminin 5-1-1 levels were decreased in RT treated tumors compared to NRT controls (p<0.005) further indicating that the RT-derived microenvironments supported HSPC differentiation into M2 macrophages. Overall, these studies define a new understanding of tumor biology in which tumor-associated HSPCs are an essential component of tumor progression and survival and identify new treatment strategies to overcome these effects and achieve more optimal clinical outcomes.
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