Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease

该提案的目的是开发强效和选择性激酶DYRK 1A抑制剂，以治疗轻度至中度 阿尔茨海默病（AD）。一组令人信服的数据表明，过度磷酸化的tau蛋白是毒性的介质 在AD中。p-Tau种类可显著影响许多细胞事件。他们主要参与了 神经纤维缠结（NFT），其存在与疾病进展密切相关。的一个重要问题 剩下的就是tau蛋白是如何过度磷酸化的DYRK 1A是一种双重特异性激酶，tau蛋白作为其底物。 DYRK 1A活性可能参与AD的发病机制，因为：（1）DYRK 1A是一种以tau蛋白为底物的激酶; (2)它在CNS神经元中强烈表达;（3）在AD中的细胞质中发现增加的DYRK 1A免疫反应性， 内嗅皮层、海马和新皮层的神经元核;（4）它的存在与增加 （5）DYRK 1A诱导的tau磷酸化降低tau稳定微管的能力;和 (6)DYRK 1A诱导的tau磷酸化促进自聚集和纤维化。DYRK1A 通过已知有助于AD发病机制的GSK 3 β激酶“引发”tau蛋白的额外磷酸化。这些 研究结果支持了我们的假设，即抑制DYRK 1A活性将改善疾病， AD患者的生活 尽管p-tau在AD发病机制中起作用，但很少有制药工业的努力是针对调节AD发病机制。 DYRK1A。Avanti Biosciences专门专注于DYRK 1A，旨在发现小分子 DYRK 1A负调节剂来源于天然儿茶素。绿色茶的主要成分，表没食子儿茶素没食子酸酯 表没食子儿茶素没食子酸酯（EGCG）是DYRK 1A的有效变构负调节剂，其导致激酶活性降低。不幸的是， 表没食子儿茶素没食子酸酯是相对不稳定的代谢和实现低大脑暴露。去发现新的儿茶素， 活性与改进的药物样性质，我们的特点是儿茶素在绿色茶，发现表没食子儿茶素不是 最有效的儿茶素事实上，反式儿茶素衍生物没食子儿茶素没食子酸酯（GCG）和儿茶素没食子酸酯（GC） 更有效，更稳定，可能会达到更好的大脑暴露。我们建议修改这些天然儿茶素， 提高效力、代谢稳定性和脑生物利用度。选定的先导化合物将被验证为阴性 在体外和rTg 4510 tau蛋白病模型中的DYRK 1A活性调节剂。这些研究旨在支持未来 IND使DYRK 1A的有效负调节剂的研究和最终的AD临床试验成为可能。

The objective of this proposal is to develop potent and selective inhibitors of the kinase, DYRK1A, to treat mild to moderate Alzheimer’s disease (AD). A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD. p-Tau species may significantly impact a number of cellular events. Prominently, they participate in the formation of neurofibrillary tangles (NFTs), whose presence is closely linked with disease progression. An important question that remains is how tau is hyperphosphorylated. DYRK1A is a dual specificity kinase for which tau serves as a substrate. DYRK1A activity may be involved in AD pathogenesis because: (1) DYRK1A is a kinase for which tau serves as substrate; (2) it is robustly expressed in CNS neurons; (3) increased DYRK1A immunoreactivity is found in AD in the cytoplasm and nucleus of neurons of the entorhinal cortex, hippocampus and neocortex; (4) its presence there is associated with increased phosphorylation of tau; (5) DYRK1A-induced phosphorylation of tau reduces tau’s ability to stabilize microtubules; and (6) DYRK1A-induced phosphorylation of tau promotes self-aggregation and fibrillization. Significantly, DYRK1A ‘primes’ tau for additional phosphorylation by GSK3β kinase which is known to contribute to AD pathogenesis. These findings support our hypothesis that inhibition of DYRK1A activity will be disease-modifying and significantly impact on the lives of those with AD. In spite of a role for p-tau in AD pathogenesis, few pharmaceutical industry efforts are targeting the modulation of DYRK1A. Avanti Biosciences is specifically and uniquely focused on DYRK1A and aims to discover small molecule DYRK1A negative modulators derived from natural catechins. The main ingredient of green tea, epigallocatechin gallate (EGCG), is a potent allosteric negative modulator of DYRK1A that results in decreased kinase activity. Unfortunately, EGCG is relatively unstable metabolically and achieves low brain exposure. To discover new catechins that exert the same activity with improved drug-like properties, we characterized the catechins in green tea and discovered that EGCG was not the most potent catechin. In fact, the trans catechin derivatives Gallocatechin gallate (GCG) and Catechin gallate (GC) were more potent, more stable and may achieve better brain exposure. We propose to modify these natural catechins to improve potency, metabolic stability, and brain bioavailability. Selected lead compounds will be validated as negative modulators of DYRK1A activity in vitro and in the rTg4510 tauopathy model. These studies are intended to support future IND enabling studies of potent negative modulators of DYRK1A and eventual AD clinical trials.