Caspase-2 Probe Compounds

项目摘要摘要 Caspase-2与中风、阿尔茨海默氏症、帕金森氏症和 亨廷顿病、神经母细胞瘤、神经眼科和额颞痴呆。宽阔的，长的- 我们工作的长期目标是开发特异性的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，这将使我们能够显示特定的 小分子探针降低caspase-2活性的药理作用 表型，最初在动物模型中。我们的具体目标都是针对caspase-2的发现和发展 但每个探测器都有不同的起点。我们将使用∆tau314水平的测量，一个特定的 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有效性 在牢房里。我们的探头设计和开发将具有三条平行的化合物表征和 优化，每一个都会通知另一个关于影响特异性和效力的caspase-2结合。 我们的三个目标是开发(1)caspase-2特异性切割的蛋白质的探针，(2)探针 来自HTS后续，以及(3)来自已知选择性caspase-2抑制剂的探针。我们在这些方面的目标都是 制备在靶蛋白上具有体外效力&100 nm的探针或工具化合物，拥有&gt；30倍 相对于同一家族中与序列相关的靶标的选择性，已经被用来分析一个“行业-- 与药物相关的非靶点的标准“小组，并已在&lt；1的细胞中展示了靶点效应 为了证明在体内的相关性，我们将使用Morris水迷宫在rTg4510小鼠身上测试这些探针， 一个公认的认知模型。我们预计这些专门针对caspase-2的探针将恢复 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 探索与caspase-2活性有关的广泛的神经疾病。 这将构成重要的纵向进步，并推动治疗学的制药发展 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.