Design of nonpeptidic topomimetics of antiangiogenic proteins with antitumor activities.
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.
Dings
Ruud P M
RP
Department of Biochemistry, 6-155 Jackson Hall, University of Minnesota, 321 Church Street, Minneapolis, MN 55455, USA
Chen
Xuemei
X
Hellebrekers
Debby M E I
DM
van Eijk
Loes I
LI
Zhang
Ying
Y
Hoye
Thomas R
TR
Griffioen
Arjan W
AW
Mayo
Kevin H
KH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D047250:Calixarenes / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D010455:Peptides; D011506:Proteins / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D010455:Peptides; D011506:Proteins; C111993:betapep-25 protein, synthetic; C530377:compound 0118; D047250:Calixarenes