Developing antiangiogenic compounds
Ehlers, Tedman James
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Angiogenesis has been identi ed as a crucial process in the growth and spread of cancers. There are many regulators of angiogenesis and their role is not yet fully understood. It has been shown that small molecule binding of the enzyme methionine aminopeptidase type II (MetAP2) results in the inhibition of endothelial cell proliferation. From a drug design prospective, this enzyme is an attractive target. Fumagillin and ovalicin, known natural products, bind with an IC50 in low nanomolar concentrations. Crystal structures of the bound complexes provide 3-dimensional coordinates for advanced computational studies. Semi-synthetic fumagillin derivatives, e.g. TNP-470, have been shown to have better drug properties, but have yet to make it through clinical trials successfully. Previous work within our lab has resulted in the preparation of novel multicyclic analogs of fumagillin. With the early development of drug analogs, it is important to verify the feasibility of molecular binding, as well as provide a rational for subsequent modi cation to produce more e ective binding. With the information that can be obtained from a proper model, potential drugs can be examined in silico. Additional work has led to the discovery of aromatic enones and dienones that show a remarkable ability to inhibit endothelial cell proliferation. These compounds are related to the natural product curcumin, which has been shown to inhibit angiogenesis in vivo. With a growing experimental data set, computational tools examining possible structure-activity relationships have been used to examine and accelerate the optimization of these compounds.