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

• 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
• 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

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(申请人提供)：全球约有6500万人患有癫痫。这些人中有三分之一以上对当前的药物治疗没有反应；因此，需要新的治疗剂。虽然已知某些脑损伤，如创伤性脑损伤、中风和癫痫持续状态(SE)易患癫痫，但目前还没有有效的干预措施来降低此类损伤后发生癫痫的风险。我们和其他人已经证实，在导致癫痫的脑损伤后，Janus Kinase(JAK)/信号转导和转录激活因子(STAT)信号通路的激活发生在海马区。使用大鼠颞叶癫痫(TLE)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JAK/STAT通路抑制剂WP1066可以减少4周内STAT的激活和自发发作的频率。虽然WP1066是一个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)性质的限制。我们最初的构效关系研究已经确定了一种新的WP1066类似物，它具有更高的稳定性，我们有初步证据表明，这种类似物以及两种已知的小分子JAK/STAT抑制剂正在临床试验或FDA批准中，它们可以导致更高的脑浓度，并比WP1066更有效地抑制SE后STAT3的激活。我们建议检测这些新的JAK/STAT抑制剂以确定1)它们抑制原代海马神经元JAK/STAT通路激活和细胞毒性的效力，2)脑内浓度随剂量和时间的变化，在脑内阻断急性癫痫诱导的JAK/STAT通路激活的能力和对其他激酶的特异性/靶外效应，以及3)这些新的JAK/STAT抑制剂对大鼠TLE模型癫痫发展和认知共病的影响。预期的结果是鉴定出可用于癫痫疾病修饰的临床试验的JAK/STAT先导抑制剂。