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

描述（由申请人提供）：全球约有6500万人患有癫痫。超过三分之一的人对目前的药物治疗没有反应；因此，需要新的治疗药物。虽然已知某些脑损伤，如创伤性脑损伤、中风和长时间癫痫状态（SE）易致癫痫，但目前没有有效的干预措施来降低此类损伤后癫痫的风险。我们和其他人已经确定，在导致癫痫的脑损伤后，海马体中会发生Janus激酶(JAK)/信号换能器和转录激活因子（STAT）信号通路的激活。利用大鼠颞叶癫痫（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时外周给药WP1066（一种JAK/STAT通路抑制剂）可以降低STAT激活和自发发作频率，持续4周。虽然它是一种有用的分子，用于展示概念验证，但WP1066受到非常不利的化学和药代动力学（PK）性质的限制。我们最初的结构-活性关系研究已经确定了一种新的WP1066类似物，它增加了稳定性，我们有初步证据表明，这种类似物，以及两种已知的小分子量JAK/STAT抑制剂，正在临床试验或FDA批准，导致更高的脑浓度，比WP1066更有效地抑制SE后STAT3的激活。我们建议研究这些新的JAK/STAT抑制剂，以确定1)它们抑制JAK/STAT通路激活和初级海马神经元细胞毒性的效力，2)脑浓度作为剂量和时间的函数，阻断急性发作诱导的大脑JAK/STAT通路激活的能力和对其他激酶的特异性/脱靶效应，以及3)这些新的JAK/STAT抑制剂对癫痫发展和认知共病的影响。预期的结果是确定JAK/STAT抑制剂的先导，可以推进癫痫疾病治疗的临床试验。

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.