Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice

Michelle A. Blaskovich, Qing Lin, Frederic L. Delarue, Jiazhi Sun, Hyung Soon Park, Domenico Coppola, Andrew D. Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

We have designed a molecule, GFB-111, that binds to platelet-derived growth factor (PDGF), prevents it from binding to its receptor tyrosine kinase, and blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases, and DNA synthesis. GFB-111 is highly potent (IC50 = 250 nM) and selective for PDGF over EGF, IGF-1, aFGF, bFGF, and HRGβ (IC50 values > 100 μM), but inhibits VEGF-induced Flk-1 tyrosine phosphorylation and Erk1/Erk2 activation with an IC50 of 10 μM. GFB-111 treatment of nude mice bearing human tumors resulted in significant inhibition of tumor growth and angiogenesis. The results demonstrate the feasibility of designing novel growth factor-binding molecules with potent anticancer and antiangiogenic activity.

Original languageEnglish (US)
Pages (from-to)1065-1070
Number of pages6
JournalNature Biotechnology
Volume18
Issue number10 SUPPL.
DOIs
StatePublished - 2000

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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