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- Title
Design of growth factor antagonists with antiangiogenic and antitumor properties.
- Authors
Sebti, Saïd M; Hamilton, Andrew D
- Abstract
This review describes our recent efforts in the development of novel therapies for cancer. Our primary approach is to design synthetic agents that antagonize the function of growth factors that are critically involved in oncogenesis and angiogenesis. We achieve this by designing synthetic molecules that can recognize the exterior surface of the growth factor and so block the interaction with its receptor tyrosine kinase. A key step is the construction of synthetic agents that contain a large (>400Å2) and functionalized surface area to recognize a complementary surface on the target growth factor. In the course of this work we have discovered a molecule, GFB-111, that binds to PDGF, prevents it from binding to its receptor tyrosine kinase, blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases and DNA synthesis. The binding affinity for PDGF is high (IC50=250 nM) and selective over EGF, IGF-1, aFGF, bFGF and HRGβ. In nude mouse models GFB-111 also shows significant inhibition of tumor growth and angiogenesis. Oncogene (2000) 19, 6566–6573.
- Subjects
NEOVASCULARIZATION; TYROSINE; CANCER treatment; CANCER; CARCINOGENESIS
- Publication
Oncogene, 2000, Vol 19, Issue 56, p6566
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204121