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The fibroblast growth factor receptors (FGFRs) are cell surface receptors with intrinsic tyrosine kinase activity, which is necessary for receptor activation and signal propagation. PD 173074 is a potent and selective inhibitor of FGFR tyrosine kinase activity, blocking autophosphorylation of FGFR1 with an IC50 value of 21.5 nM.1 For comparison, it weakly inhibits PDGFR and c-Src (IC50 = 17.6 and 19.8 μM, respectively) and has no effect on EGFR, InsR, MEK, or PKC.1 PD 173074 also prevents signaling, at nanomolar levels, through FGFR2-5.2,3,4,5,6 Inhibition of FGFR signaling using PD 173074, impairs angiogenesis5,2 as well as self-renewal of stem cells via ERK1/2 activation.7,8,6
1
Mohammadi, M., Froum, S., Hamby, J.M., et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J17(20)5896-5904(1998).
2
Skaper, S.D., Kee, W.J., Facci, L., et al. The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. J Neurochem751520-1527(2000).
3
Koziczak, M., Holbro, T., and Hynes, N.E. Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene233501-3508(2004).
4
Grand, E.K., Chase, A.J., Heath, C., et al. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia18962-966(2004).
5
St.Bernard, R., Zheng, L., Liu, W., et al. Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology146(3)1145-1153(2005).
6
Stavridis, M.P., Lunn, J.S., Collins, B.J., et al. A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. Development1342889-2894(2007).
7
Kunath, T., Saba-El-Leil, M.K., Almousailleakh, M., et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development1342895-2902(2007).
8
Zaragosi, L., Ailhaud, G., and Dani, C. Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells. Stem Cells242412-2419(2006).
Zaragosi, L., Ailhaud, G., and Dani, C. Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells. Stem Cells242412-2419(2006).
Kunath, T., Saba-El-Leil, M.K., Almousailleakh, M., et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development1342895-2902(2007).
Stavridis, M.P., Lunn, J.S., Collins, B.J., et al. A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. Development1342889-2894(2007).
St.Bernard, R., Zheng, L., Liu, W., et al. Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology146(3)1145-1153(2005).
Grand, E.K., Chase, A.J., Heath, C., et al. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia18962-966(2004).
Koziczak, M., Holbro, T., and Hynes, N.E. Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene233501-3508(2004).
Mohammadi, M., Froum, S., Hamby, J.M., et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J17(20)5896-5904(1998).
Skaper, S.D., Kee, W.J., Facci, L., et al. The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. J Neurochem751520-1527(2000).