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）：全世界大约有 6500 万人患有癫痫症。其中超过三分之一的人对当前的药物治疗没有反应；因此，需要新的治疗剂。尽管已知某些脑损伤，如创伤性脑损伤、中风和长期癫痫持续状态（SE）容易诱发癫痫，但目前尚无有效的干预措施来降低此类损伤后发生癫痫的风险。我们和其他人已经确定，在导致癫痫的脑损伤后，海马体中会激活 Janus 激酶 (JAK)/信号转导器和转录激活器 (STAT) 信号通路。使用颞叶癫痫（TLE）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质。我们观察到，在 SE 时外周给予 WP1066（一种 JAK/STAT 通路抑制剂）可降低 STAT 激活和自发性癫痫发作频率，持续 4 周。虽然 WP1066 是一种用于展示概念验证的有用分子，但它受到非常不利的化学和药代动力学 (PK) 特性的限制。我们最初的结构-活性关系研究已经确定了 WP1066 的一种新型类似物，该类似物具有更高的稳定性，并且我们有初步证据表明该类似物以及正在进行临床试验或 FDA 批准的两种已知的小分子量 JAK/STAT 抑制剂，结果与 WP1066 相比，其脑浓度更高，并且在 SE 后更有效地抑制 STAT3 激活。我们建议检查这些新型 JAK/STAT 抑制剂，以确定 1) 它们抑制原代海马神经元中 JAK/STAT 通路激活和细胞毒性的效力，2) 脑浓度作为剂量和时间的函数，以及阻止急性癫痫发作的能力。大脑中 JAK/STAT 通路的激活以及对其他激酶的特异性/脱靶效应，以及 3) 这些新型 JAK/STAT 抑制剂对大鼠 TLE 模型中癫痫发展和认知共病的影响。预期结果是鉴定出主要的 JAK/STAT 抑制剂，这些抑制剂可以推进癫痫疾病修饰的临床测试。