Design of growth factor antagonists with antiangiogenic and antitumor properties

Saïd M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)6566-6573
Number of pages8
JournalOncogene
Volume19
Issue number56
DOIs
StatePublished - Dec 27 2000

Keywords

  • Angiogenesis
  • Cancer drug discovery
  • Oncogenesis
  • Platelet-derived growth factor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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