In Vivo Probes of Sphingosine Kinase Function

描述（由申请人提供）：鞘氨醇激酶（SphK 1、SphK 2）合成鞘氨醇1-磷酸（S1 P），这是一种生物活性脂质，可控制淋巴细胞从次级淋巴组织中的排出，并可能影响心率和内皮屏障功能。通过操纵其潜在的mRNA或基因来改变SphK蛋白水平，这表明该酶参与了多种令人困惑的信号级联反应和疾病过程。这些研究表明，需要药物样SphK抑制剂来更好地了解S1 P生物学，并了解阻断SphK活性是否会影响疾病模型中的病理过程。然而，目前缺乏这样的化学工具，但对于将人类SphKs作为潜在治疗靶点的决策至关重要。我们有领先的SphK 1和SphK 2抑制剂，具有强效和同种型选择性。这些化合物在体内达到其目标并迅速调节循环S1 P水平，提供了一种极好的药效学生物标志物，指示化合物的药代动力学。我们的平台在合成操作方面是易于处理的，我们已经开发出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。我们经验丰富的团队由药物化学家（桑托斯）和药理学家（林奇）组成，他们可以在此成功的基础上迅速实现优化的SphK 1和SphK 2抑制剂。具体而言，我们将通过迭代合成和测试来改进我们的抑制剂系列，以获得高效（KI 10 nM）同种型选择性（> 100倍）抑制剂，这些抑制剂在动物中具有足够的持久性，可以每天给药一次。我们产生的化合物将为研究人员提供严格测试的机会，即通过抑制一种（或两种）SphK同种型来调节S1 P水平是一种有前途的治疗策略。

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.