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JNCI Journal of the National Cancer Institute 2006 98(13):932-936; doi:10.1093/jnci/djj247
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© The Author 2006. Published by Oxford University Press.

BRIEF COMMUNICATION

Design of Nonpeptidic Topomimetics of Antiangiogenic Proteins With Antitumor Activities

Ruud P. M. Dings, Xuemei Chen, Debby M. E. I. Hellebrekers, Loes I. van Eijk, Ying Zhang, Thomas R. Hoye, Arjan W. Griffioen, Kevin H. Mayo

Affiliations of authors: Departments of Biochemistry, Molecular Biology & Biophysics (RPMD, KHM) and Chemistry (XC, TRH) and the Cancer Center (YZ, KHM), University of Minnesota, Minneapolis, MN; Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, University Hospital Maastricht, The Netherlands (DMEIH, LIvE, AWG)

Correspondence to: Kevin H. Mayo, PhD, Department of Biochemistry, 6-155 Jackson Hall, University of Minnesota, 321 Church Street, Minneapolis, MN 55455 (e-mail: mayox001{at}umn.edu).

The inhibition of angiogenesis is a promising avenue for cancer treatment. Although some angiostatic compounds are in the process of development and testing, these often prove ineffective in vivo or have unwanted side effects. We have designed, synthesized, and evaluated a small library of nonpeptidic, calixarene-based protein surface topomimetics that display chemical substituents to approximate the molecular dimensions and amphipathic features (hydrophobic and positively charged residues) of the antiangiogenic peptide anginex, which, like many antiangiogenic proteins, consists primarily of an antiparallel beta-sheet structure as the functional unit. Two of the topomimetics (0118 and 1097) were potent angiogenesis inhibitors in vitro, as determined by endothelial cell proliferation, migration, and chick embryo chorioallantoic membrane assays. Moreover, both compounds were highly effective at inhibiting tumor angiogenesis and growth in two mouse models (MA148 human ovarian carcinoma and B16 murine melanoma). Our results demonstrate the feasibility of designing nonpeptidic protein surface topomimetics as novel pharmaceutical agents for clinical intervention against cancer through angiostatic or other mechanisms.


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