Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, USA.
J Med Chem. 2010 Feb 11;53(3):1056-66. doi: 10.1021/jm9012328.
Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.
自分泌酶（ATX，NPP2）最近被证明是负责合成生物活性脂质溶血磷脂酸（LPA）的溶血磷脂酶 D。LPA 在癌症中具有明确的作用，并且 LPA 的产生与 ATX 的促进癌症作用一致。在许多癌细胞类型中都发现了 ATX 和 LPA 受体表达的增加。本研究结合基于配体的计算方法（二元定量构效关系）、药物化学和实验酶测定，对先前鉴定的小分子 ATX 抑制剂 H2L 7905958（1）进行了优化。通过计算筛选分析了 70 种预期的类似物，其中 30 种有前途的化合物被合成并进行筛选，以评估其疗效、效力和抑制机制。这种方法已经确定了四种与先导化合物一样有效或更有效的类似物。最有效的类似物对 ATX 介导的 FS-3 水解的 IC50 为 900 nM，Ki 为 700 nM，使该化合物的效力比先前描述的先导化合物约高 3 倍。
