Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
 

 

Target Validation Information
TTD IDTTDS00411
Target NameMacrophage colony-stimulating factor receptor    
Type of TargetSuccessful target    
Drug Potency against TargetN-(2-morpholinophenyl)-5-nitrofuran-2-carboxamideIC50 = 1100 nM[1]
PKC-412IC50 = 142 nM[2]
MLN-518IC50 = 3430 nM[3]
The Effect of Target Knockout, Knockdown or Genetic VariationsThe biological role of M-CSF in vivo has been studied mostly using the mutant osteopetrotic (op/op) mice, a natural model of M-CSF knock out. In op/op mice, the total absence of M-CSF production is due to the insertion of a single base pair in the coding region of the M-CSF gene. The op/op mice are characterized by skeletal abnormalities, impaired fertility, low body weight, toothless phenotype and a severe deficiency in mature macrophages and osteoclasts. Repeated injections of recombinant h uMan M-CSF (rhM-CSF) to op/op mice correct osteopetrosis and the toothless phenotype, osteoclasts and restore normal n uMbers of spleen and femoral macrophages, but have no effect on the deficiencies of pleural and peritoneal macrophages or on the reduced female fertility. Thus, in vivo, soluble M-CSF induces the proliferation, differentiation and bone resorbing activity of osteoclasts from earlier hematopoietic progenitors. However, in vitro, soluble M-CSF increases migration, chemotaxis, spreading and survival, but reduces the resorbing activity of isolated osteoclasts [120, 121]. This suggests that other forms of M-CSF or other cytokines acting in combination with it, may contribute to the physiological regulation of osteoclast activity. This hypothesis is reinforced by the fact that it has been possible to purify the PG-M-CSF isoform from bone matrix and that cultured osteoblasts synthesize membrane and matrix-bound M-CSF.[4]
Ref 1Bioorg Med Chem Lett. 2007 Nov 15;17(22):6070-4. Epub 2007 Sep 19.Potent 2'-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents. To Reference
Ref 2Bioorg Med Chem. 2010 Mar 1;18(5):1789-97. Epub 2010 Jan 28.Colony stimulating factor-1 receptor as a target for small molecule inhibitors. To Reference
Ref 3J Med Chem. 2002 Aug 15;45(17):3772-93.Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. To Reference
Ref 4Eur Cytokine Netw. 1997 Jun;8(2):125-36.Macrophage colony-stimulating-factor (M-CSF or CSF-1) and its receptor: structure-function relationships. To Reference



 

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