Salk Institute for Biological Studies, La Jolla, CA, USA.
Virogenics, Inc., San Diego, CA, USA.
J Alzheimers Dis. 2024;101(s1):S179-S192. doi: 10.3233/JAD-231062.
Old age is the major risk factor for sporadic Alzheimer's disease (AD). However, old age-related changes in brain physiology have generally not been taken into consideration in developing drug candidates for the treatment of AD. This is at least partly because the role of these age-related processes in the development and progression of AD are still not well understood. Nevertheless, we and others have described an association between the oxytosis/ferroptosis non-apoptotic regulated cell death pathway and aging. Based on this association, we incorporated protection against this pathway as part of a cell-based phenotypic screening approach to identify novel drug candidates for the treatment of AD. Using this approach, we identified the fisetin derivative CMS121 as a potent neuroprotective molecule that is able to maintain cognitive function in multiple pre-clinical models of AD. Furthermore, we identified a key target of CMS121 as fatty acid synthase, a protein which had not been previously considered in the context of AD. Herein, we provide a comprehensive description of the development of CMS121, its preclinical activities, and the results of the toxicology testing that led to its IND approval.
衰老（ageing）是散发性阿尔茨海默病（AD）的主要危险因素。然而，在开发治疗 AD 的药物候选物时，通常没有考虑到与年龄相关的大脑生理学变化。这至少部分是因为这些与年龄相关的过程在 AD 的发展和进展中的作用仍不明确。尽管如此，我们和其他人已经描述了氧化/铁死亡非凋亡调节细胞死亡途径与衰老之间的关联。基于这种关联，我们将针对该途径的保护作为基于细胞的表型筛选方法的一部分，以确定治疗 AD 的新型药物候选物。使用这种方法，我们确定了 fisetin 衍生物 CMS121 作为一种有效的神经保护分子，能够在多个 AD 的临床前模型中维持认知功能。此外，我们确定了 CMS121 的一个关键靶标是脂肪酸合酶（fatty acid synthase），这是一种以前在 AD 背景下没有被考虑过的蛋白质。本文全面描述了 CMS121 的开发、其临床前活性以及导致其 IND 批准的毒理学测试结果。
