Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484798
Title: Kinase inhibitors of the FMS receptor for macrophage colony stimulating factor
Author: Brownlow, Nicola
ISNI:       0000 0000 7157 2090
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Abstract:
FMS is the receptor for macrophage colony stimulating factor (M-CSF or CSF-1) and is essential for the differentiation and survival of most macrophages, microglia and osteoclasts Infiltration of macrophages and high levels of M-CSF in serum are associated with poor prognosis in human breast, ovarian and endometrial cancers. Consequently, inhibitors of FMS have considerable therapeutic potential for the treatment of cancer, as well as macrophage-mediated inflammatory disease and bone disorders caused by excessive osteoclastogenesis . Here I report the identification of four clinically advanced small molecule kinase inhibitors which can also target FMS, as shown by various biochemical and cell-based assays. The inhibitors I identified are imatinib, nilotinib, tandutinib and dasatinib (IC50s = 600, 250, 400 and 0.5 nM, respectively), where the IC50 values refer to inhibition of FMS-dependent cell growth. All of these inhibitors effectively inhibited osteoclastogenesis at concentrations expected to be achieved in patients and nilotinib was a particularly potent inhibitor (IC50 = 50 nM) indicating that nilotinib is a strong candidate for treatment of diseases where osteoclasts are over activated such as osteoporosis and osteolytic bone disease. Dasatinib was found to be a potent inhibitor of tumour associated macrophages derived from ovarian tumour ascites (IC50 = 0.5 nM) which is similar to the concentration required to inhibit FMS and within concentrations considered to be achieved in vivo. Using these FMS inhibitors I have also confirmed that the downregulation of the FMS receptor in response to ligand binding is independent of kinase activity and instead requires a structural change in the receptor. Intriguingly, at least two tyrosine autophosphorylation sites of FMS are still phosphorylated in the presence of some of these inhibitors and therefore in the absence of FMS kinase activity. This implies that other kinases may be involved in FMS activation.
Supervisor: Dibb, Nick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.484798  DOI: Not available
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