Abstract
Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell factor receptor were inhibited with an IC50 of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms-like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC50 of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.
Footnotes
- Abbreviations:
- PDGF
- platelet-derived growth factor
- PDGFR
- platelet-derived growth factor receptor
- CHO
- Chinese hamster ovary
- CSF-1R
- colony-stimulating factor-1 receptor
- c-Kit
- stem cell factor receptor
- Flt3
- fms-like tyrosine kinase-3
- VEGFR-2
- vascular endothelial growth factor receptor 2
- RT-PCR
- reverse transcription-polymerase chain reaction
- FGFR-1
- fibroblast growth factor receptor-1
- mAb
- monoclonal antibody
- EGFR
- epidermal growth factor receptor
- EGF
- epidermal growth factor
- FGF
- fibroblast growth factor
- PK
- protein kinase
- bFGF
- basic fibroblast growth factor
- MAPK
- mitogen-activated protein kinase
- Received March 2, 2001.
- Accepted June 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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