Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 305-764, Republic of Korea.
LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea.
Eur J Med Chem. 2018 Mar 25;148:397-409. doi: 10.1016/j.ejmech.2018.02.049. Epub 2018 Feb 17.
Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.
自主分泌酶（Autotaxin，ATX）是治疗多种癌症的潜在靶点。本研究基于前期研究，对一系列新型 ATX 抑制剂进行了合理设计和合成。讨论了该系列的生物评价和构效关系（SAR）。在所合成的 14 个衍生物中，6 个化合物（2、3、4、12、13 和 14）对 ATX 的抑制活性增强，IC 值在纳摩尔低浓度范围内。通过分子对接研究研究了所有合成化合物在 ATX 活性部位的分子相互作用。在此，我们描述了我们的先导化合物优化工作，该工作确定了一种有效的 ATX 抑制剂（化合物 4 的 IC=1.23nM，FS-3 和 2.18nM，双-pNPP）。此外，还对该最有前途的化合物的药代动力学特性进行了分析。
