X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States.
X-Rx, Inc., 430 East 29th Street, Suite 1060, New York, New York 10016, United States.
J Med Chem. 2020 Jul 23;63(14):7840-7856. doi: 10.1021/acs.jmedchem.0c00688. Epub 2020 Jul 9.
The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.
分泌型磷酸二酯酶 autotaxin 的活性会产生炎症信号分子 LPA，并与多种人类疾病相关，包括特发性肺纤维化 (IPF)。我们筛选了一个包含 2.25 亿种化合物的单 DNA 编码化学文库 (DECL)，并鉴定出了一系列有效的抑制剂。对该系列化合物的优化导致发现了化合物 （X-165），这是一种高效、选择性和可生物利用的小分子。化合物 与人类 autotaxin 的共结晶表明，它具有一种新的结合模式，占据 autotaxin 活性位点附近的疏水口袋和通道。化合物 在纳摩尔水平抑制了人血浆和鼠血浆中 LPA 的产生，并在人类肺纤维化的小鼠模型中显示出疗效。在成功完成 IND 研究后，化合物 获得了 FDA 的批准，进入了 I 期临床试验。这些结果表明，DECL 命中物可以很容易地优化成临床候选药物。
