Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX–LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.

中文翻译：

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绑定到疏水域和催化域中的通道的有效体内自分泌抑制素抑制剂的鉴定。

Autotaxin（ATX，也称为ENPP2）是体内主要的溶血磷脂酸（LPA）产生酶，LPA调节各种生理功能，例如血管生成和伤口愈合，以及病理功能，包括增殖，转移和通过特定的LPA受体引起纤维化。因此，ATX-LPA轴是许多疾病的有希望的治疗靶标，包括癌症，肺和肝纤维化以及神经性疼痛。先前的结构研究表明，ATX的催化结构域具有疏水口袋和疏水通道。这些用于识别底物溶血磷脂酰胆碱（LPC），并将生成的LPA传递至质膜上的LPA受体。大多数报道的ATX抑制剂与疏水口袋或疏水通道结合。在这里体外和体内。值得注意的是，我们的抑制剂可以挽救过表达ATX的斑马鱼胚胎中的card门（两心）表型。