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Colony stimulating factor 1 receptor (CSF1R, c-Fms, CD115) is a tyrosine kinase transmembrane receptor for a cytokine called colony stimulating factor 1 (CSF-1). CSF-1R and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity.

In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

PLX-3397 (pexidartinib) is an oral, potent, multi-target receptor tyrosine kinase inhibitor of CSF-1R, Kit, and Flt3 and is the most advanced selective CSF-1R inhibitor under clinical development. ABT-869 (linifanib) is an oral inhibitor of CSF-1R tyrosine kinase conducted a phase II trial in which ABT869 was administered to patients with hepatocellular carcinoma. BLZ-945 is another orally active, bioavailable, potent, and selective inhibitor of CSF-1R, which is currently being assessed in a first-in-man phase I/II study as a single agent or in combination with PDR-001 (anti-PD-1 antibody) in several advanced solid tumors. Besides, multiple anti-CSF-1R monoclonal antibodies have also entered clinical trials, including FPA-008 (cabiralizumab), RG-7155 (RO5509554), IMC-CS4 (LY3022855) and AMG-820.

The development of new CSF-1R/CSF-1 axis inhibitors represents an attractive method for managing patients with metastatic solid tumors refractory to the standards of care or with diffuse/relapsed TGCT. Recent clinical trials testing CSF-1R inhibitors as monotherapies have shown encouraging results in the management of PVNS but disappointing outcomes for the treatment of solid tumors.

 

References:

1. Peyraud F, et al. Curr Oncol Rep. 2017 Sep 5;19(11):70.

2. Pyonteck SM, et al. Nat Med. 2013 Oct;19(10):1264-72.

3. Kogan M, et al. Anticancer Res. 2012 Mar;32(3):893-9.

4. Albert DH, et al. Mol Cancer Ther. 2006 Apr;5(4):995-1006.

 

Cat. No. Product Name CAS No. Information
PC-61373

Edicotinib

1142363-52-7

Edicotinib (JNJ 40346527, PRV 6527) is a potent, selective, orally bioavailable CSF-1R inhibitor with IC50 of 3.2 nM; shows weak affinity for KIT and FLT3 (IC50= 20 nM and 190 nM, respectively); reduces the levels of EMT-associated genes, stem cell markers and chemoresistance genes, produces strong chemo-sensitizing effects in vitro and in vivo.

Rheumatoid Arthritis

Phase 2 Clinical

PC-36143

JTE-952

1255303-54-8 JTE-952 (JTE952) is a potent, selective colony stimulating factor-1 receptor (CSF1R) type II inhibitor with IC50 of 14 nM, shows cellular activity in BMMCs IL-6 secretion assays with IC50 of 20 nM; JTE-952 is also effective against a mouse collagen-induced model of arthritis (mouse CIA-model).
PC-35232

AZD7507

1041852-85-0 AZD7507 (AZD-7507) is a potent, selective, orally available CSF-1R (c-FMS) with IC50 of 32 nM; demonstrates cleaner secondary pharmacology profiles, demonstrates good rat oral PK, with in vivo clearance of 7 ml/min/kg and 42% bioavailability; has an IC50 >20 uM in the canine L-type Ca channel assays; causes shrinkage of established tumors and increases mouse survival in genetic PDAC model.
PC-63412

JNJ-28312141 hydrochloride

JNJ-28312141 is a potent, orally active CSF-1 receptor (CSF-1R) kinase inhibitor with IC50 of 0.69 nM; shows narrow kinase selectivity profile, also potently inhibits KIT (IC50=5 nM), AXL (12 nM), TRKA (15 nM), FLT3 (30 nM), and LCK (88 nM); inhibits CSF-1-induced CSF-1R phosphorylation with IC50 of 5 nM, inhibits CSF-1-dependent proliferation of mouse macrophages and CSF-1-induced expression of MCP-1 by human monocytes with IC50 of 3 nM; inhibits the ITD-FLT3-dependent proliferation of MV-4-11 cells with IC50 of 21 nM, inhibits FLT3 ligand-induced FLT3 phosphorylation in recombinant Baf3 cells with IC50 of 76 nM; demonstrates potential therapeutic activity in AML, solid tumors and bone metastases in vivo.
PC-63411

JNJ-28312141

885692-52-4 JNJ-28312141 is a potent, orally active CSF-1 receptor (CSF-1R) kinase inhibitor with IC50 of 0.69 nM; shows narrow kinase selectivity profile, also potently inhibits KIT (IC50=5 nM), AXL (12 nM), TRKA (15 nM), FLT3 (30 nM), and LCK (88 nM); inhibits CSF-1-induced CSF-1R phosphorylation with IC50 of 5 nM, inhibits CSF-1-dependent proliferation of mouse macrophages and CSF-1-induced expression of MCP-1 by human monocytes with IC50 of 3 nM; inhibits the ITD-FLT3-dependent proliferation of MV-4-11 cells with IC50 of 21 nM, inhibits FLT3 ligand-induced FLT3 phosphorylation in recombinant Baf3 cells with IC50 of 76 nM; demonstrates potential therapeutic activity in AML, solid tumors and bone metastases in vivo.
PC-43376

c-FMS-IN-8

885704-21-2 c-FMS-IN-8 is a potent, selective c-FMS kinase inhibitor with IC50 of 0.8 nM, shows activity in collagen-induced model of arthritis in mice.
PC-43194

BLZ945

953769-46-5 BLZ945 (BLZ-945) is a potent, selective, brain-penetrant CSF-1R inhibitor with biochemical IC50 of 1 nM, displays >3,200-fold selectivity over other kinases (c-Kit, PDGFR-β, Flt3, Abl, etc.); inhibits CSF-1-dependent proliferation in bone marrow-derived macrophages (BMDMs) with EC50 of 67 nM, and decreases CSF-1R phosphorylation; blocks glioma progression and significantly improves survival, efficiently limits tumor progression combining with PD-1/PD-L1 blocking antibodies in neuroblastoma.

Solid Tumors

Phase 2 Clinical

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