Division of Cell Biology, Netherlands Proteomics Centre, Centre of Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7257-62. doi: 10.1073/pnas.1001529107. Epub 2010 Apr 1.
Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC(50) approximately 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.
自分泌酶（Autotaxin，ATX）是一种分泌型核苷酸磷酸二酯酶/磷酸酶，可作为溶血磷脂酶 D 发挥作用，生成脂质介质溶血磷脂酸（LPA），LPA 是许多细胞类型的有丝分裂原、趋化因子和存活因子。ATX-LPA 信号轴与血管生成、慢性炎症、纤维化疾病和肿瘤进展有关，这使得该系统成为治疗的一个有吸引力的靶点。然而，目前尚无有效的、选择性的非脂类 ATX 抑制剂。通过筛选化学文库，我们发现了噻唑烷二酮类化合物，它们可在体外和体内选择性抑制 ATX 介导的 LPA 生成。在抑制剂中加入硼酸部分后，其抑制活性大约提高了 100 倍（IC50 约为 30 nM），硼酸部分设计用于靶向 ATX 的活性位点苏氨酸（T210）。将该抑制剂静脉注射到小鼠体内，可使血浆 LPA 水平迅速下降，这表明循环中 LPA 的周转率比以前认为的要快得多。因此，基于硼酸的小分子有望成为靶向 ATX 的候选药物。
