Caspase-2 Probe Compounds

项目摘要 半胱天冬酶-2与神经学适应症如中风、阿尔茨海默氏症、帕金森氏症和帕金森病有关。 亨廷顿病、神经母细胞瘤、神经眼科学和额颞叶痴呆。宽，长- 我们工作的长期目标是开发特异性caspase-2抑制剂作为神经治疗剂。这 长期目标取决于首先开发caspase-2探针，使我们能够显示特定的 通过小分子探针药理学降低胱天蛋白酶-2活性导致疾病的改善 表型，最初在动物模型中。我们的具体目标都是针对caspase-2的发现和开发 但每个人都有不同的出发点。我们将使用测量314能级， 治疗和临床相关的生物标志物，作为我们测试漏斗的一部分，以衡量我们的探针的功效 在细胞中。我们的探针设计和开发将采用三种平行的化合物表征路径， 优化，其中每一个将告知另一个关于影响特异性和效力的半胱天冬酶-2结合。 我们的三个目标是：（1）从caspase-2特异性切割的蛋白质中开发探针，（2）探针 来自HTS后续，和（3）来自已知的选择性半胱天冬酶-2抑制剂的探针。我们的目标是 产生探针或工具化合物，其对靶蛋白具有<100 nM的体外效力，具有>30倍的 相对于同一家族中序列相关靶的选择性，已经针对“工业- 这是药理学相关脱靶的“标准”组，并且已经在<1 µM。为了证明体内相关性，我们将使用Morris水迷宫在rTg 4510小鼠中测试这些探针， 一个完善的认知模型。我们希望这些特异性靶向caspase-2的探针能够恢复 这些老年小鼠的认知能力没有明显的副作用。最终，我们将使用这些特定的caspase-2 探针，以调查广泛的神经系统疾病，其中半胱天冬酶-2活性已牵连。 这将构成一个重要的纵向进步，并刺激药物治疗的发展 这将对人类健康产生积极影响。

Project Summary Abstract Caspase-2 has been implicated in neurological indications such as stroke, Alzheimer's, Parkinson's, and Huntington's diseases, neuroblastoma, neuro-ophthalomology, and frontotemporal dementia. The broad, long- term objective of our work is the development of specific caspase-2 inhibitors as neuro-therapeutic agents. This long-term objective hinges on first developing caspase-2 probes that will allow us to show that specific pharmacological reduction of caspase-2 activity by small molecule probes leads to the amelioration of disease phenotype, initially in animal models. Our specific aims all target the discovery and development of caspase-2 probes but each has a different starting point. We will use measurement of ∆tau314 levels, a specific therapeutically- and clinically-relevant biomarker, as part of our testing funnel, to gauge the efficacy of our probes in cells. Our probe design and development will feature three parallel paths of compound characterization and optimization, each of which will inform the other as to caspase-2 binding that influences specificity and potency. Our three aims are to develop (1) probes from proteins that are specifically cleaved by caspase-2, (2) probes from HTS follow-on, and (3) probes from known selective caspase-2 inhibitors. Our goal in each of these is to produce a probe or tool compound which has in vitro potency <100 nM at the target protein, possesses >30-fold selectivity relative to sequence-related targets in the same family, has been profiled against an “industry- standard” panel of pharmacologically-relevant off-targets, and has demonstrated on-target effect in cells of <1 µM. To demonstrate in vivo relevance, we will test these probes in rTg4510 mice using the Morris water maze, a well-established model of cognition. We expect that these probes that specifically target caspase-2 will restore cognition in these aged mice without observable side effects. Ultimately, we will use these specific caspase-2 probes to investigate the broad range of neurological disorders in which caspase-2 activity has been implicated. This will constitute and important vertical advancement and spur the pharmaceutical development of therapeutics that will positively impact human health.