Multiparameter optimization of new phenothiazines for proteasome activation

阿尔茨海默病(AD)等神经退行性疾病没有治疗选择。目前的治疗方法只是暂时抑制疾病症状。我们在药物发现方面开创了一种新的范式，涉及激活20S蛋白酶体，该蛋白酶体针对与神经退行性疾病的发病机制相关的特定蛋白。由于缺乏合适的线索，这种治疗方法的翻译在很大程度上还没有被探索。这项工作填补了这一空白。 我们的实验室确定了迄今为止报道的最有效的20s激活剂。HIT化合物能激活20S蛋白酶体的蛋白分解活性(~10倍！)并在体外和细胞培养中诱导α-突触核蛋白和tau(参与AD发病机制的最重要的蛋白质)的降解，而不影响正常的结构蛋白。我们假设，专注于效力和理化性质的优化将使我们能够产生第一个具有药物样性质的20S激活剂，适合在体内翻译这一神经退行性疾病的新治疗策略。 在这项探索性的R21拨款中，我们将通过(1)效率的点击到领先的优化，以及(2)吩噻嗪支架的物理化学优化来完成多参数优化工作，以生成具有适合CNS化学空间的参数的类药物候选药物。 这项工作的成功完成将产生合适的类药物候选药物，以探索一种全新的治疗方法，目标是一种仍被认为不可用药的独特蛋白质类别。

There are no treatment options for neurodegenerative diseases such as Alzheimer’s disease (AD). Current treatments only temporarily suppress disease symptoms. We are pioneering a new paradigm in drug discovery that involves activation of the 20S proteasome, which targets specific proteins associated in the pathogenesis of neurodegenerative diseases. The translation of this therapeutic approach has been largely unexplored due to the lack of suitable leads. This work addressed that void. Our lab identified the most potent 20S activator reported to date. The hit compound activates the proteolytic activity of the 20S proteasome (~10 fold!) and induces the degradation of alpha-synuclein and tau (most notable protein involved in the pathogenesis of AD) in vitro and cell culture without affecting normal structured proteins. We hypothesize that optimization focused on both potency and physicochemical properties will allow us to generate the first 20S activator with drug-like properties suitable for in vivo translation of this new therapeutic strategy for neurodegenerative diseases. In this exploratory R21 grant, we will complete a multiparameter optimization effort by (1) hit-to- lead optimization of potency, and (2) physicochemical optimization of the phenothiazine scaffold to generate drug-like candidates with suitable parameters for CNS chemical space. Successful completion of this work will generate suitable drug-like candidates to explore an entirely new therapeutic approach that targets a unique class of proteins still deemed, undruggable.