Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
复制标题
DOI：
10.1021/acs.jmedchem.0c00688
复制
发表时间：
2020-07-23
影响因子：
7.3
通讯作者：
Zhang, Ying
中科院分区：
文献类型：
--
作者：
Cuozzo, John W.;Clark, Matthew A.;Zhang, Ying
分泌的磷酸二酯酶自分泌运动因子的活性产生炎性信号分子LPA，并且与包括特发性肺纤维化（IPF）在内的许多人类疾病相关。我们筛选了一个含有2.25亿种化合物的DNA编码化学库（DECL），并鉴定了一系列有效的抑制剂。这一系列的优化导致了化合物1（X-165）的发现，这是一种高效，选择性和生物可利用的小分子。化合物1与人自分泌运动因子的共沉淀证明其具有占据自分泌运动因子活性位点附近的疏水口袋和通道的新型结合模式。化合物1以纳摩尔水平抑制人和小鼠血浆中LPA的产生，并且在人肺纤维化的小鼠模型中显示出功效。在成功完成IND使能研究后，化合物1被FDA批准进行I期临床试验。这些结果表明，DECL命中可以容易地优化为临床候选。
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 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 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 1 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 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.