Improving in vivo stability of sphingosine kinase inhibitors

描述（由申请人提供）：我们和其他人假设抑制SphK1是一种强大的治疗策略，以细胞增生为特征的病理，如癌症和纤维化。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。鞘氨酸激酶1型（SphK1）在人类疾病的动物模型中涉及多种疾病过程，如癌症和纤维化。SphynKx Therapeutics （SKX）已获得专利许可，以脒为基础的SphK1抑制剂具有强效（~100 nM）和选择性（~500倍），但这些抑制剂在体内代谢迅速，因此不是最佳的。在此，我们概述了一系列策略，包括前药形式，修饰脒，胍类等，使SphK1抑制剂具有药物样。这些新的化学实体将首先在SphK1活性的破细胞和全细胞试验中进行测试，如果合适的话，将在大鼠身上进行药代动力学分析。经过优化的类似药物的SKX抑制剂将使其类似药物，从而使该项目的第二阶段成为可能，即在动物疾病模型中测试SphK1抑制剂。这些药物需要验证SphK1作为药物靶点，并确定SKX化合物作为研究新药。

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.