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  • Recent studies investigating the effects of mesenchymal


    Recent studies investigating the effects of mesenchymal stem cell (MSC) therapy in rodent models including chronic renal failure and glomerulonephritis have demonstrated that MSC therapy can result in beneficial effects [57], [58]. In cats, autologous intra-renal injections of either adipose tissue-derived or bone-marrow-derived mesenchymal stem cells demonstrated modest improvements in glomerular filtration rate (GFR) and serum biochemical markers of renal disease [59]. MSCs are highly proliferative, undifferentiated cells that can self-renew [60], [61]. Due to these properties, MSCs are being suggested as therapeutic options for a range of diseases including chronic renal failure in cats [59], [62]. CSF-1 mRNA and protein are constitutively expressed [63], [64], [65] and, given the trophic functions, would be candidate mediators of some of the effects of MSC. Previous studies using non-species-specific colony stimulating factors for therapy have been hampered by the development of auto-antibodies. For example, the administration of rhGM-CSF to healthy dogs has been reported to produce neutralising Verdinexor receptor after 10–12days [66]. Similarly, the administration of rhGM-CSF to cats with FIV triggered neutralising antibodies in 75% of the cats, 35days after a 2-week treatment protocol [67]. A practical therapy for cats based upon CSF-1R agonist is likely to involve the production of the species-specific protein, but this is costly. For therapeutic trials, our data shows that human and pig CSF-1 or IL-34 would have similar efficacy and could be considered for potential therapy. For acute therapy, the generation of neutralising antibodies may not be a significant issue. In conclusion, we have developed an in vitro system for the study of feline macrophages which will allow further investigation of macrophage related diseases and the effects of therapy on these cells. The feline CSF-1R has been cloned and expressed in Ba/F3 cells and used to assess the activity of non-species-specific CSF-1 and IL-34. This assay also offers the possibility of screening for antagonists, including blocking antibodies, which might have applications in inflammatory disease and malignancy [1].
    Acknowledgements This work forms part of a BBSRC Case Studentship (BBSRC Grant Number: 338BCB R40954) undertaken at the Roslin Institute and Royal (Dick) School of Veterinary Studies, in collaboration with Pfizer Animal Health, Kalamazoo, USA.
    Colony-stimulating factor-1 receptor (CSF-1R or cFMS) is a receptor tyrosine kinase whose expression is restricted to macrophages, osteoclasts and trophoblasts and which is uniquely responsible for mediating the growth differentiation and survival effects of monocyte colony stimulating factor-1 (CSF-1). CSF-1 signals through its receptor by means of ligand-induced dimerization and subsequent autophosphorylation. Macrophage proliferation, activation and survival are believed to be important for the progression of diseases such as rheumatoid arthritis (RA), osteoporosis, inflammatory bowel disease, and cancer. Thus, a reduction in the number of synovial macrophages through inhibition of CSF-1R signaling is expected to be therapeutic in RA, related inflammatory diseases, and cancer., There are a number of CSF-1R inhibitors with in vivo antiinflammatory efficacy reported in the literature, including ,, , ,,, and ., As a part of our program targeting CSF-1R for RA, our internal kinase-targeted compound library was screened measuring the inhibition of autophosphorylation of CSF-1R in a cell-based assay. Compounds and were identified as potent inhibitors of CSF-1R (IC=40nM and 57nM, respectively). However, the high molecular weights (MW=524–525) and poor ligand efficiencies (LE=0.27–0.28) of these two hits required significant structural modifications to maximize their potential as leads. The work described herein demonstrates the utility of structure-based drug design (SBDD) in shifting the binding mode of this series from DFG-in to a DFG-out binding mode resulting in novel potent CSF-1R kinase inhibitor leads.