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In Vivo Probes of Sphingosine Kinase Function

鞘氨醇激酶功能的体内探针

基本信息

批准号：
8918686
负责人：
KEVIN R. LYNCH
金额：
$ 36.82万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-13 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918686
关键词：
Algorithms Alleles Alzheimer&apos s Disease Animal Disease Models Animals Biochemical Markers Biological Assay Biological Markers Biology Blood Blood Circulation Blood Vessels Cells Chemicals Computer Simulation Disease Disease model Dose Drug Kinetics Drug Targeting Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Extravasation Fibroblasts Fibrosis Genes Goals Guanidines Health Heart Rate Human In Vitro Investigation Knockout Mice Lead Learning Libraries Lipids Lymphocyte Lymphoid Tissue Malignant Neoplasms Messenger RNA Metabolic Metabolism Modeling Molecular Molecular Biology Molecular Genetics Motivation Mus Pathologic Processes Pathology Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phosphotransferases Process Property Protein Isoforms Proteins Recombinants Research Personnel Series Signal Transduction Sphingosine Synthesis Chemistry System Testing Therapeutic Veterans Wild Type Mouse analog base chemical synthesis chemotherapy drug development enzyme activity improved in vivo indexing inhibitor/antagonist innovation lipid mediator liquid chromatography mass spectrometry meetings programs research study scaffold sphingosine 1-phosphate sphingosine kinase success therapeutic target tool trafficking

项目摘要

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.

描述（由申请人提供）：鞘氨醇激酶（SphK1、SphK2）合成 1-磷酸鞘氨醇 (S1P)，这是一种生物活性脂质，可控制淋巴细胞从次级淋巴组织的流出，并可能影响心率和内皮屏障功能。通过操纵其底层 mRNA 或基因而改变 SphK 蛋白水平，表明该酶参与了各种令人眼花缭乱的信号级联和疾病过程。此类研究表明需要类药物 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中的病理进程。然而，目前缺乏此类化学工具，但对于将人类 SphK 作为潜在治疗靶点的决策至关重要。我们拥有领先的 SphK1 和 SphK2 抑制剂，它们有效且具有同种型选择性。这些化合物在体内击中目标并快速调节循环 S1P 水平，提供了一种出色的药效生物标志物，可指示化合物的药代动力学。我们的平台在合成操作方面易于处理，并且我们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名药物化学家 (Santos) 和一名药理学家 (Lynch) 组成，他们可以在这一成功的基础上迅速实现优化的 SphK1 和 SphK2 抑制剂。具体来说，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，这些抑制剂在动物体内具有足够的持久性，允许每天给药一次。我们生成的化合物将为研究人员提供严格测试这一想法的机会，即通过抑制一种（或两种）SphK 同种型来调节 S1P 水平是一种有前途的治疗策略。