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），一种生物活性脂质，可控制二级淋巴样淋巴细胞的出口，并可能影响心率和内皮障碍物的功能。 SPHK蛋白水平通过操纵其潜在mRNA或基因的变化暗示了这种酶在各种信号级联和疾病过程中令人困惑的酶中。这样的研究表明，需要类似药物的SPHK抑制剂以更好地了解S1P生物学，并了解刺激性SPHK活性是否影响疾病模型中的病理学进程。但是，目前缺乏此类化学工具，但对于为人类SPHK作为潜在治疗靶标的决定提供了重要的决定。我们具有有效且具有选择性的铅SPHK1和SPHK2抑制剂。这些化合物在体内达到了靶标，并迅速调节循环的S1P水平，提供了一种出色的药效生物标志物，可以索引复合药代动力学。我们的平台在合成操作方面是可以处理的，我们已经开发了一种强大的算法来赢得不合格化合物，从而有效地识别了最有用的化学探针。我们的资深团队组成了一名药物化学家（Santos）和一名药物学家（Lynch），他们可以迅速建立在这一成功的基础上，以实现优化的SPHK1和SPHK2抑制剂。具体而言，我们将通过迭代合成和测试的迭代回合来改进我们的抑制剂系列，以获得高度有效的（Ki 10 nm）同种型选择性（> 100倍）的抑制剂，这些抑制剂在动物中足够持久，以便每天给药一次。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同种型来调节S1P水平的想法，这是一种有希望的治疗策略。