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Improving in vivo stability of sphingosine kinase inhibitors

提高鞘氨醇激酶抑制剂的体内稳定性

基本信息

批准号：
8315010
负责人：
Timothy L MacDonald
金额：
$ 15.28万
依托单位：
SPHYNKX THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8315010
关键词：
Amides Amidines Animal Disease Models Animal Model Animals Apoptosis Area Biological Assay Biological Markers Brain Businesses Cell Cycle Arrest Cells Ceramides Chemicals Clinical Colon Disease Disease Progression Drops Drug Delivery Systems Drug Exposure Drug Kinetics Equilibrium Fibrosis G-Protein-Coupled Receptors Genotoxic Stress Goals Guanidines Half-Life Hour Intravenous Bolus Investigational Drugs Lead Licensing Lipids Liver Lung Malignant Neoplasms Measurement Measures Modeling Molecular Mus Oral Ovary Pathology Pharmaceutical Preparations Pharmacology Phase Phosphorylation Positioning Attribute Process Prodrugs Proliferating Property Proteolysis Publications RNA Rattus Reporting Role Science Signal Transduction Sphingosine Stomach Structure Testing Therapeutic Time Work analog angiogenesis base chemical synthesis design human disease improved in vitro Assay in vitro testing in vivo inhibitor/antagonist kinase inhibitor malignant breast neoplasm mouse model phase 1 study phase 2 study pre-clinical response small molecule sphingosine 1-phosphate sphingosine kinase tumor

项目摘要

DESCRIPTION (provided by applicant): We and others have hypothesized that inhibiting SphK1 is a powerful therapeutic strategy in pathologies that are characterized by cell hyperproliferation, e.g. cancer and fibrosis. This hypothesis was generated largely through the use interfering RNA strategies - there is a paucity of potent, selective small molecule inhibitors of SphKs. Sphingosine kinase type 1 (SphK1) has been implicated in a variety of disease processes in animal models of human diseases such as cancer and fibrosis. SphynKx Therapeutics (SKX) has licensed proprietary, amidine-based SphK1 inhibitors that are both potent (~100 nM) and selective (~500 fold), but these are suboptimal in that they are metabolized rapidly in vivo. Herein we outline a set of strategies including pro-drug forms, modified amidines, guanidines, etc. to render the SphK1 inhibitors drug like. These new chemical entities will be tested first in broken and whole cell assays of SphK1 activity and, if suitable, taken into rats for pharmacokinetic analysis. The optimized, drug-like SKX inhibitors to make them drug-like will enable phase II of the project, i.e. testing an SphK1 inhibitor in animal models of disease. Such drugs are required to validate SphK1 as a drug target and to identify the SKX compound to take forward as an Investigational New Drug. PUBLIC HEALTH RELEVANCE: Sphingosine kinase type 1 (SphK1) has been implicated in a variety of disease processes in animal models of human disease such as cancer and fibrosis. Until recently, high potency small molecule inhibitors of SphK1 were not available. SphynKx Therapeutics (SKX) has proprietary SphK1 inhibitors that are both selective and potent. However, the current SKX inhibitors are suboptimal in that they are metabolized rapidly in vivo. The current proposal outlines a plan to optimize the lead SKX inhibitors to make them drug-like and thus enable the next phase of this work - testing the inhibitors in animal models of disease. Such inhibitors are required to validate SphK1 inhibition as a drug target and to identify the SKX compound to take forward as an Investigational New Drug.

描述（由申请人提供）：我们和其他人假设，抑制SphK 1是以细胞过度增殖为特征的病理学（例如癌症和纤维化）的有效治疗策略。这一假设主要是通过使用干扰RNA策略产生的-缺乏有效的、选择性的SphKs小分子抑制剂。鞘氨醇激酶1型（SphK 1）已被牵连在人类疾病的动物模型，如癌症和纤维化的各种疾病过程。SphynKx Therapeutics（SKX）已获得专利，基于脒的SphK 1抑制剂，既有效（~100 nM）又具有选择性（~500倍），但这些抑制剂在体内代谢迅速，因此不是最佳的。在此，我们概述了一组策略，包括前药形式，修饰的脒，胍等，使SphK 1抑制剂药物样。这些新化学实体将首先在SphK 1活性的破碎细胞和全细胞测定中进行测试，如果合适的话，将其带入大鼠体内进行药代动力学分析。优化的药物样SKX抑制剂使其具有药物样作用，将使该项目的第二阶段成为可能，即在动物疾病模型中测试SphK 1抑制剂。这些药物需要验证SphK 1作为药物靶标，并确定SKX化合物作为研究性新药。公共卫生相关性：鞘氨醇激酶1型（SphK 1）已被牵连在人类疾病的动物模型，如癌症和纤维化的各种疾病过程。直到最近，SphK 1的高效小分子抑制剂还不可用。SphynKx Therapeutics（SKX）拥有专有的SphK 1抑制剂，具有选择性和有效性。然而，目前的SKX抑制剂是次优的，因为它们在体内代谢迅速。目前的提案概述了一项优化主要SKX抑制剂的计划，使其具有药物样作用，从而使这项工作的下一阶段能够在动物疾病模型中测试抑制剂。需要此类抑制剂来验证SphK 1抑制作为药物靶标，并鉴定SKX化合物作为研究性新药。