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 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.
StatePublished - 2000

Fingerprint

Platelet-Derived Growth Factor
Platelets
Human Activities
Inhibitory Concentration 50
Tumors
Molecules
Bearings (structural)
Chemical activation
Polynucleotide 5'-Hydroxyl-Kinase
Platelet-Derived Growth Factor Receptors
Neoplasms
Phosphorylation
Receptor Protein-Tyrosine Kinases
Insulin-Like Growth Factor I
Epidermal Growth Factor
Nude Mice
Vascular Endothelial Growth Factor A
Tyrosine
Intercellular Signaling Peptides and Proteins
DNA

Keywords

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

ASJC Scopus subject areas

  • Microbiology

Cite this

Blaskovich, M. A., Lin, Q., Delarue, F. L., Sun, J., Park, H. S., Coppola, D., ... Sebti, S. M. (2000). Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. Nature Biotechnology, 18(10 SUPPL.), 1065-1070.

Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. / Blaskovich, Michelle A.; Lin, Qing; Delarue, Frederic L.; Sun, Jiazhi; Park, Hyung Soon; Coppola, Domenico; Hamilton, Andrew; Sebti, Saïd M.

In: Nature Biotechnology, Vol. 18, No. 10 SUPPL., 2000, p. 1065-1070.

Research output: Contribution to journalArticle

Blaskovich, MA, Lin, Q, Delarue, FL, Sun, J, Park, HS, Coppola, D, Hamilton, A & Sebti, SM 2000, 'Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice', Nature Biotechnology, vol. 18, no. 10 SUPPL., pp. 1065-1070.
Blaskovich, Michelle A. ; Lin, Qing ; Delarue, Frederic L. ; Sun, Jiazhi ; Park, Hyung Soon ; Coppola, Domenico ; Hamilton, Andrew ; Sebti, Saïd M. / Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice. In: Nature Biotechnology. 2000 ; Vol. 18, No. 10 SUPPL. pp. 1065-1070.
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