Discovery of novel FMS kinase inhibitors as anti-inflammatory agents

Illig, Carl R.; Chen, Jinsheng; Wall, Mark J.; Wilson, Kenneth J.; Ballentine, Shelley K.; Rudolph, Matthias; DesJarlais, Renée L.; Chen, Yanmin; Schubert, Carsten J.; Petrounia, Ioanna P.; Crysler, Carl; Molloy, Christopher J.; Chaikin, Margery A.; Manthey, Carl L.; Player, Mark R.; Tomczuk, Bruce E.; Meegalla, Sanath K.

doi:10.1016/j.bmcl.2008.01.059

Cited by 42 publications

(56 citation statements)

References 11 publications

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“…A small molecule inhibitor of c-fms kinase activity (30 mg/kg, PO) was used to reduce monocyte/macrophage proliferation, differentiation and survival, based on published reports. 30,57 …”

Section: Mouse Model Of Bilateral Renal Irimentioning

confidence: 99%

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Clements¹,

Gershenovich²,

Chaber³

et al. 2016

Journal of the American Society of Nephrology

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Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemiareperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b + cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis.

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“…A small molecule inhibitor of c-fms kinase activity (30 mg/kg, PO) was used to reduce monocyte/macrophage proliferation, differentiation and survival, based on published reports. 30,57 …”

Section: Mouse Model Of Bilateral Renal Irimentioning

confidence: 99%

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Clements¹,

Gershenovich²,

Chaber³

et al. 2016

Journal of the American Society of Nephrology

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“…Kinase Assays Assays used to determine the IC 50 values for CSF-1R, FLT3, KIT, AXL, and TRKA were carried out using a fluorescence polarization competition immunoassay format and have been described previously (23). Briefly, for CSF-1R, CSF-1R(538-972) encompassing the tyrosine kinase domain was expressed and purified from a baculovirus system (28).…”

Section: Jnj-28312141 4-cyano-n-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethmentioning

confidence: 99%

“…Cells were stimulated 16 h with 100 ng/ mL recombinant human CSF-1 (R&D Systems), and secreted MCP-1 was measured by ELISA (R&D Systems). Mouse macrophages were derived from bone marrow as described (23). Macrophages suspended in EMEM containing 10% FBS were plated at a density of 5,000 cells per well into Costar 96-well tissue culture plates.…”

Section: Jnj-28312141 4-cyano-n-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethmentioning

confidence: 99%

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JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia

Manthey

Johnson

Illig

et al. 2009

Molecular Cancer Therapeutics

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103

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There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colonystimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/ 80 + tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.

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“…Iressa was obtained from AstraZeneca. A novel CSF-1R receptor inhibitor, 4-cyano-1H-pyrrole-2-carboxylic acid [4-(4- (17). Two additional novel CSF-1R inhibitors, PLX3397 and PLX5622, were provided by Plexxikon.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling

Coniglio

Eugenín

Dobrenis

et al. 2012

Mol Med

362

297

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Glioblastoma multiforme is a deadly cancer for which current treatment options are limited. The ability of glioblastoma tumor cells to infiltrate the surrounding brain parenchyma critically limits the effectiveness of current treatments. We investigated how microglia, the resident macrophages of the brain, stimulate glioblastoma cell invasion. We first examined the ability of normal microglia from C57Bl/6J mice to stimulate GL261 glioblastoma cell invasion in vitro. We found that microglia stimulate the invasion of GL261 glioblastoma cells by approximately eightfold in an in vitro invasion assay. Pharmacological inhibition of epidermal growth factor receptor (EGFR) strongly inhibited microglia-stimulated invasion. Furthermore, blockade of colony stimulating factor 1 receptor (CSF-1R) signaling using ribonucleic acid (RNA) interference or pharmacological inhibitors completely inhibited microglial enhancement of glioblastoma invasion. GL261 cells were found to constitutively secrete CSF-1, the levels of which were unaffected by epidermal growth factor (EGF) stimulation, EGFR inhibition or coculture with microglia. CSF-1 only stimulated microglia invasion, whereas EGF only stimulated glioblastoma cell migration, demonstrating a synergistic interaction between these two cell types. Finally, using PLX3397 (a CSF-1R inhibitor that can cross the blood-brain barrier) in live animals, we discovered that blockade of CSF-1R signaling in vivo reduced the number of tumor-associated microglia and glioblastoma invasion. These data indicate that glioblastoma and microglia interactions mediated by EGF and CSF-1 can enhance glioblastoma invasion and demonstrate the possibility of inhibiting glioblastoma invasion by targeting glioblastoma-associated microglia via inhibition of the CSF-1R.

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Discovery of novel FMS kinase inhibitors as anti-inflammatory agents

Cited by 42 publications

References 11 publications

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia

Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling

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