Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease
Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease
复制标题
STAT5/6 Src同源性2 （SH2）小分子靶向抑制变应性气道疾病
DOI：
10.1074/jbc.ra117.000567
复制
发表时间：
2018-06-29
影响因子：
4.8
通讯作者：
McMurray, John S.
中科院分区：
文献类型：
--
作者：
Knight, J. Morgan;Mandal, Pijus;McMurray, John S.
哮喘是一种肺部和气道的慢性炎症性疾病，也是所有慢性疾病中最严重的疾病之一。先前的研究已经确定，实验性哮喘和人类哮喘的表达需要IL-4/IL-13/IL-4受体（IL-4R）信号通路，该通路激活转录因子STAT6。然而，目前还没有针对这一重要途径的小分子处于临床开发阶段。为此，我们利用临床前哮喘模型，试图在小鼠和人类 STAT6 中开发并测试 Src 同源 2 结构域的小分子抑制剂。我们之前在阻断STAT6与IL-4R的对接位点以及STAT6中Tyr(641)磷酸化的基础上开发了多种拟肽化合物。在这里，我们扩大了最初的体外结构-活性关系研究的范围，将这些肽的中心和 C 末端类似物纳入其中，以开发先导化合物 PM-43I。使用 PM-43I 进行初始剂量范围、毒性和药代动力学实验，我们发现它能有效抑制小鼠体内 STAT5 和 STAT6 依赖性过敏性气道疾病。此外，PM-43I 逆转了小鼠先前存在的过敏性气道疾病，其 ED50 最低为 0.25 g/kg。值得注意的是，PM-43I 可通过肾脏有效清除，且无长期毒性。我们得出的结论是，PM-43I 是一类小分子中的第一个，可能适合进一步针对哮喘的临床开发。
Asthma is a chronic inflammatory disease of the lungs and airways and one of the most burdensome of all chronic maladies. Previous studies have established that expression of experimental and human asthma requires the IL-4/IL-13/IL-4 receptor (IL-4R) signaling pathway, which activates the transcription factor STAT6. However, no small molecules targeting this important pathway are currently in clinical development. To this end, using a preclinical asthma model, we sought to develop and test a small-molecule inhibitor of the Src homology 2 domains in mouse and human STAT6. We previously developed multiple peptidomimetic compounds on the basis of blocking the docking site of STAT6 to IL-4R and phosphorylation of Tyr(641) in STAT6. Here, we expanded the scope of our initial in vitro structure-activity relationship studies to include central and C-terminal analogs of these peptides to develop a lead compound, PM-43I. Conducting initial dose range, toxicity, and pharmacokinetic experiments with PM-43I, we found that it potently inhibits both STAT5- and STAT6-dependent allergic airway disease in mice. Moreover, PM-43I reversed preexisting allergic airway disease in mice with a minimum ED50 of 0.25 g/kg. Of note, PM-43I was efficiently cleared through the kidneys with no long-term toxicity. We conclude that PM-43I represents the first of a class of small molecules that may be suitable for further clinical development against asthma.