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

Nature Biotechnology volume 18, pages 1065–1070 (2000)Cite this article

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.

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Figure 1: Structure of growth factor binders (GFBs).
Figure 2: GFB-111 binds PDGF and inhibits 125I-PDGF binding to its receptor on NIH 3T3 cells.
Figure 3: GFB-111 inhibits selectively PDGF-stimulated receptor tyrosine autophosphorylation and activation of MAPK.
Figure 4: GFB-111 selectively inhibits PDGF-stimulated DNA synthesis.
Figure 5: GFB-111 inhibits tumor growth and angiogenesis in nude mice.

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Acknowledgements

This work was supported by NIH PO1 CA78038-01A1 and United States Army grant DAMD17-99-1-9458. We would also like to thank Dr. Axel Ullrich (Max-Planck-Institute for Biochemistry) and Dr. Richard Jove (Moffitt Cancer Center and USF) for NIH3T3 cells overexpressing the VEGF/flk-1 receptor and EGFR, respectively.

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Authors and Affiliations

  1. Departments of Biochemistry and Molecular Biology and of Pathology, Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, 33612, FL

    Michelle A. Blaskovich, Frederic L. Delarue, Jiazhi Sun, Domenico Coppola, Andrew D. Hamilton & Saïd M. Sebti

  2. Department of Chemistry, Yale University, New Haven, 06511, CT

    Qing Lin & Hyung Soon Park

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  1. Michelle A. Blaskovich
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Correspondence to Andrew D. Hamilton or Saïd M. Sebti.

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Blaskovich, M., Lin, Q., Delarue, F. et al. Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. Nat Biotechnol 18, 1065–1070 (2000). https://doi.org/10.1038/80257

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