DEMETRIOS T BRADDOCK
Medical Practice at Blf Vw Dr, Guilford, CT

2011011, May 12, 2011

Jun 15, 2009

12/993397

Demetrios Braddock - Guilford CT, US

A61K 31/675, C07F 9/6558, C07F 9/655, C07C 39/15, C07D 311/86, C07C 323/20, C07D 327/08, C07F 9/74, C07C 63/331, A61K 31/665, A61K 31/055, A61K 31/352, A61K 31/10, A61K 31/39, A61K 31/285, A61K 31/194, A61P 35/00, A61P 35/02, A61K 39/395, A61K 31/404, A61K 31/44, A61K 31/4439, A61K 31/506, A61K 38/20, A61K 38/46, A61K 33/24, A61K 38/21

424 852, 544243, 549220, 568726, 549392, 568 48, 549 16, 556 73, 562488, 514 85, 514100, 514735, 514454, 514712, 514434, 514504, 514568, 4241331, 514414, 514350, 514338, 514275, 424 946, 424649, 424 857

Autotaxin (ATX) is a prometastatic enzyme initially isolated from the conditioned media of human melanoma cells that stimulates a myriad of biological activities including angiogenesis and the promotion of cell growth, survival, and differentiation through the production of lysophosphatidic acid (LPA). ATX increases the aggressiveness and invasiveness of transformed cells, and ATX levels directly correlate with tumor stage and grade in several human malignancies. To study the role of ATX in the pathogenesis of malignant melanoma, we developed antibodies and small molecule inhibitors against recombinant human protein. Immunohistochemistry of paraffin embedded human tissue demonstrates that ATX levels are markedly increased in human primary and metastatic melanoma relative to benign nevi. Chemical screens identified several small molecule inhibitors with binding constants ranging from nanomolar to low micromolar. Cell migration and invasion assays with melanoma cell lines demonstrate that ATX markedly stimulates melanoma cell migration and invasion, an effect suppressed by ATX inhibitors. The migratory phenotype can be rescued by the addition of ATX's enzymatic product, LPA, confirming that the observed inhibition is linked to suppression of LPA production by ATX. Chemical analogues of the inhibitors demonstrate structure activity relationships important for ATX inhibition and indicate pathways for their optimization. These studies suggest that ATX is an approachable molecular target for the rational design of chemotherapeutic agents directed against human malignancies driven by the ATX/LPA axis, especially including malignant melanoma, among numerous others including breast and ovarian cancers.