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    SMALL MOLECULE INHIBITORS OF AUTOTAXIN AND METHODS OF USE
    7.
    发明申请
    SMALL MOLECULE INHIBITORS OF AUTOTAXIN AND METHODS OF USE 审中-公开
    自由基的小分子抑制剂及其使用方法

    公开(公告)号：US20110110886A1

    公开(公告)日：2011-05-12

    申请号：US12993397

    申请日：2009-06-15

    申请人： Demetrios Braddock

    发明人： Demetrios Braddock

    IPC分类号： A61K31/675 ,  C07F9/6558 ,  C07F9/655 ,  C07C39/15 ,  C07D311/86 ,  C07C323/20 ,  C07D327/08 ,  C07F9/74 ,  C07C63/331 ,  A61K31/665 ,  A61K31/055 ,  A61K31/352 ,  A61K31/10 ,  A61K31/39 ,  A61K31/285 ,  A61K31/194 ,  A61P35/00 ,  A61P35/02 ,  A61K39/395 ,  A61K31/404 ,  A61K31/44 ,  A61K31/4439 ,  A61K31/506 ,  A61K38/20 ,  A61K38/46 ,  A61K33/24 ,  A61K38/21

    CPC分类号： A61K31/047 ,  A61K31/10 ,  A61K31/352 ,  A61K45/06 ,  A61K2300/00

    摘要： 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.

    摘要翻译： Autotaxin（ATX）是最初从人类黑素瘤细胞的条件培养基中分离出来的一种前导酶，它刺激无数的生物学活性，包括血管生成和通过产生溶血磷脂酸（LPA）促进细胞生长，存活和分化。 ATX增加转化细胞的侵袭性和侵袭性，ATX水平与几种人类恶性肿瘤的肿瘤分期和分级直接相关。 为了研究ATX在恶性黑色素瘤发病机制中的作用，我们开发了针对重组人蛋白质的抗体和小分子抑制剂。 石蜡包埋的人体组织的免疫组织化学证实，相对于良性痣，人原发性和转移性黑素瘤中ATX水平显着增加。 化学筛选出几种具有纳摩尔至低微摩尔浓度的结合常数的小分子抑制剂。 细胞迁移和黑色素瘤细胞系侵袭测定表明ATX显着刺激黑素瘤细胞迁移和侵袭，这是ATX抑制剂抑制的作用。 迁移表型可以通过添加ATX的酶产物LPA来拯救，证实观察到的抑制与ATX产生的LPA抑制有关。 抑制剂的化学类似物表现出对ATX抑制重要的结构活性关系，并指示其优化途径。 这些研究表明ATX是针对ATX / LPA轴驱动的人类恶性肿瘤的化学治疗剂的合理设计的一个平易近人的分子靶点，特别是包括恶性黑素瘤，其中包括乳腺癌和卵巢癌。