In Vivo Probes of Sphingosine Kinase Function

描述（由申请人提供）：鞘氨醇激酶（SphK1, SphK2）合成鞘氨醇1-磷酸（S1P），这是一种生物活性脂质，控制淋巴细胞从次级淋巴组织的分泌，并可能影响心率和内皮屏障功能。通过操纵其潜在mrna或基因来改变SphK蛋白水平，暗示该酶参与了各种令人困惑的信号级联反应和疾病过程。这些研究表明，需要类似药物的SphK抑制剂，以便更好地了解S1P生物学，并了解阻断SphK活性是否会影响疾病模型的病理过程。然而，目前缺乏这样的化学工具，但对于决定是否将人类SphKs作为潜在的治疗靶点至关重要。我们有SphK1和SphK2先导抑制剂，它们是有效的和同型选择性的。这些化合物在体内击中目标并快速调节循环中的S1P水平，为化合物的药代动力学指标提供了良好的药效学生物标志物。我们的平台在合成操作方面易于处理，我们已经开发了一种强大的算法来筛选不合格的化合物，从而有效地识别最有用的化学探针。我们的资深团队由一位药物化学家（Santos）和一位药理学家（Lynch）组成，他们可以在这一成功的基础上迅速实现SphK1和SphK2抑制剂的优化。具体来说，我们将通过反复的合成和测试来改进我们的抑制剂系列，以获得高效（KI 10 nM）同型选择性（> 100倍）抑制剂，这些抑制剂在动物体内具有足够的持久性，可以每天给药一次。我们生成的化合物将使研究人员有机会严格测试通过抑制一种（或两种）SphK亚型来调节S1P水平是一种很有前途的治疗策略。

DESCRIPTION (provided by applicant): Sphingosine kinases (SphK1, SphK2) synthesize sphingosine 1-phosphate (S1P), a bioactive lipid that controls egress of lymphocytes from secondary lymphoid tissues and may influence heart rate and endothelial barrier function. Changes in SphK protein levels by manipulation of their underlying mRNAs or genes implicates the enzyme in a bewildering variety of signaling cascades and disease processes. Such studies point to a need for drug-like SphK inhibitors both to understand S1P biology better and to learn whether interdicting SphK activity influences the course of pathologies in disease models. However, such chemical tools are lacking currently but are essential to inform decisions regarding human SphKs as potential therapeutic targets. We have lead SphK1 and SphK2 inhibitors that are potent and isotype selective. These compounds hit their targets in vivo and rapidly modulate circulating S1P levels, providing an excellent pharmacodynamic biomarker that indexes compound pharmacokinetics. Our platforms are tractable regarding synthetic manipulation and we have developed a powerful algorithm to winnow substandard compounds and thereby efficiently identify the most useful chemical probes. Our veteran team consists a medicinal chemist (Santos) and a pharmacologist (Lynch) who can build on this success rapidly to realize optimized SphK1 and SphK2 inhibitors. Specifically, we will improve, by iterative rounds of synthesis and testing, our inhibitor series to obtain highly potent (KI 10 nM) isotype selective (> 100-fold) inhibitors that are sufficiently persistent in animals to permit once daily dosing. The compounds that we generate will afford researchers the opportunity to test rigorously the idea that modulation of S1P levels by inhibition of one (or both) SphK isotypes is a promising therapeutic strategy.