The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.

中文翻译：

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溶血磷脂酶自分泌运动因子的有效抑制剂的发现。


自分泌运动因子-溶血磷脂酸 (ATX-LPA) 轴与多种疾病有关，包括炎症、纤维化和癌症。这使得 ATX 成为一个有吸引力的药物靶点，其抑制可能会产生有用的治疗药物。通过高通量筛选 (HTS)，我们鉴定了一系列 ATX 小分子抑制剂，随后对其效力、选择性和可开发性进行了优化。这提供了类似药物的化合物，例如 9v (CRT0273750)，它可以调节血浆中的 LPA 水平，适合体内研究。 X射线晶体学揭示这些化合物具有意想不到的结合模式，因为它们不与活性位点锌离子相互作用，而是占据从ATX活性位点延伸的疏水性LPC口袋，同时占据LPA“出口”通道。