The overall objective of this program is the identification and development of therapeutics for metastatic diseases. This will be pursued through inhibition of the enzyme heparin which has been shown to be involved in the ability of cells to successfully invade neighboring tissue. Heparin activity appears to be critical for extravasation, cellular passage into and out of the bloodstream, as well as release of stimulatory growth factors sequestered in extra-cellular matrix. Inhibition of heparin via modified heparin fragments has been shown to reduce both inflammatory response-induced leukocytes infiltration and tumor cell metastasis, supporting the importance of this particular target for a number of relevant disease areas. The specific aims of this proposal are to characterize heparin inhibitors biochemically, to verify inhibition of enzyme activity; and then characterize them in models relating to vascular remodeling and cell invasion. These heparin inhibitors will be previously identified from a primary screen at Repligen but have not been subjected to further study. Completion of these aims would validate the goal of obtaining protein-heparan antagonists from directed combinatorial library screening. Demonstrated activity in models such as those listed above would validate Phase II aims of further compound optimization prior to clinical testing. PROPOSED COMMERCIAL APPLICATION: Characterization of new chemical entities accomplished in the workscope of this grant are predicted to have commercial applications resulting in inhibitors of metastatic diseases and solid tumor growth
