Multiparameter optimization of new phenothiazines for proteasome activation

对于阿尔茨海默病（AD）等神经退行性疾病没有治疗选择。目前的治疗只能暂时抑制疾病症状。我们正在开创一种新的药物发现范式，涉及20 S蛋白酶体的激活，其靶向与神经退行性疾病发病机制相关的特定蛋白质。由于缺乏合适的线索，这种治疗方法的翻译在很大程度上尚未探索。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20 S激活剂。命中化合物激活20 S蛋白酶体的蛋白水解活性（~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发病机制的最显著的蛋白质）的降解，而不影响正常结构的蛋白质。我们假设，集中在效能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20 S激活剂，适用于这种新的神经退行性疾病治疗策略的体内转化。 在这项探索性的R21资助中，我们将完成多参数优化工作，包括（1）效价的点击优化，以及（2）吩噻嗪支架的物理化学优化，以生成具有CNS化学空间合适参数的药物样候选物。 这项工作的成功完成将产生合适的药物样候选人，以探索一种全新的治疗方法，该方法针对一类独特的蛋白质，仍然被认为是不可治疗的。

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.