Development of novel JAK/STAT inhibitors for Epilepsy prevention and treatment

开发用于癫痫预防和治疗的新型 JAK/STAT 抑制剂

基本信息

批准号：
8659954
负责人：
Amy R. Brooks-Kayal
金额：
$ 42.61万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8659954
关键词：
Acrylamides Acute Amides Animal Model Behavior Behavioral Biological Assay Blood - brain barrier anatomy Brain Brain Injuries Cells Chemicals Clinical Clinical Trials Cognitive Comorbidity Data Decision Trees Development Disease Dose Drug Kinetics Epilepsy Epileptogenesis FDA approved Frequencies Goals Hippocampus (Brain)Hydrogen In Vitro Individual Inhibitory Concentration 50 Injury Janus kinase Lead Mediator of activation protein Medical Metabolic Modeling Modification Molecular Weight Neurons Outcome Outcome Study Pathway interactions Peripheral Permeability Phosphotransferases Pilocarpine Prevention Property Rattus Research Risk STAT protein STAT3 gene Safety Seizures Signal Pathway Signal Transduction Specificity Status Epilepticus Stroke Structure-Activity Relationship Temporal Lobe Epilepsy Testing Therapeutic Agents Time Tissues Toxic effect Transcriptional Activation Translating Traumatic Brain Injury Work analog base chemical stability chemical synthesis cognitive function effective intervention in vivo inhibitor/antagonist methyl group novel novel therapeutics pre-clinical prevent public health relevance research clinical testing screening

项目摘要

DESCRIPTION (provided by applicant): Approximately 65 million people worldwide have epilepsy. Over one-third of these individuals do not respond to current medical therapy; consequently, novel therapeutic agents are needed. Although certain brain injuries such as traumatic brain injury, stroke and prolonged status epileptics (SE) are known to predispose to epilepsy, there are currently no effective interventions to reduce the risk of epilepsy after such injuries. We and others have established that activation of the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway occurs in the hippocampus following brain injuries that lead to epilepsy. Using a rat model of temporal lobe epilepsy (TLE), we have preliminary evidence that this activation may be a critical mediator of acquired epileptogenesis. We have observed that peripheral administration of WP1066- a JAK/STAT pathway inhibitor -at the time of SE reduces both STAT activation & spontaneous seizure frequency for 4 weeks. While it was a useful molecule for displaying proof-of-concept, WP1066 is limited by highly unfavorable chemical & pharmacokinetic (PK) properties. Our initial structure- activity relationship studies have identified one novel analog of WP1066 that has increased stability, and we have preliminary evidence that this analog, as well as two known small molecular weight JAK/STAT inhibitors that are in clinical trial or FDA approved, result in higher brain concentrations and inhibit STAT3 activation after SE more effectively than WP1066. We propose to examine these novel JAK/STAT inhibitors to determine 1) their potency to inhibit JAK/STAT pathway activation and cellular toxicity in primary hippocampal neurons, 2) brain concentrations as a function of dose and time, ability to block acute seizure- induced JAK/STAT pathway activation in brain and specificity/off-target effects on other kinases, and 3) the effects of these novel JAK/STAT inhibitors on epilepsy development and cognitive co-morbidities in a rat TLE model. The expected outcome is identification of lead JAK/STAT inhibitors that can be advanced towards clinical testing for epilepsy disease modification.

描述（由申请人提供）：全球约有6500万人患有癫痫病。这些人中有超过三分之一没有对当前的医疗疗法做出反应；因此，需要新颖的治疗剂。尽管已知某些脑部损伤，例如脑损伤，中风和长期状态癫痫病（SE），但已知癫痫病，但目前尚无有效的干预措施来降低此类受伤后癫痫的风险。我们和其他人已经确定，Janus激酶（JAK）/信号换能器和转录激活因子（STAT）信号传导途径发生在导致癫痫病的脑损伤之后，海马受伤发生。使用颞叶癫痫（TLE）的大鼠模型，我们有初步证据表明这种激活可能是获得性癫痫发生的关键介体。我们已经观察到，WP1066- jak/stat途径抑制剂的外围给药 - 在SE时降低了统计激活和自发癫痫发作频率4周。尽管它是显示概念验证证明的有用分子，但WP1066受到高度不利的化学和药代动力学（PK）特性的限制。我们的初始结构 - 活性关系研究已经确定了一种提高稳定性的WP1066的一种新型类似物，我们有初步的证据表明，该类似物以及已知的两个已知的小分子量JAK/Stat抑制剂已在临床试验或FDA批准中批准，导致脑浓度更高，并且在SE SE SE的较高的STAT3激活后比WP106更有效地抑制STAT3激活。我们建议检查这些新型的JAK/Stat抑制剂，以确定1）它们抑制jak/Stat途径激活和细胞毒性的效力，在原发性海马神经元中，2）脑浓度作为剂量和时间的函数，急性癫痫发作诱导的JAK/STAT途径在大脑/特异性/特异性上的统计信息的效果，以及其他KINES效应，以及3）的作用，并在其他KINTAS上效应，以及3）效果。大鼠TLE模型中的癫痫发育和认知合并症。预期的结果是鉴定铅jak/stat抑制剂，这些抑制剂可以朝着进行癫痫疾病修饰的临床测试前进。