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- W2896172637 abstract "Alzheimer's disease (AD), the leading cause of dementia in the elderly, is a chronic, fatal, and complex neurodegenerative disorder. In recent decades, only several drugs were approved worldwide for treating AD. The failure rate of candidates in clinical trials is about 99.6% from 2002 to 2012, and particularly the failure of Solanezumab at phase III trial cast a shadow on the AD drug development. To date, most drugs approved for AD are AChE inhibitors, which could improve the level of Ach, an important neurotransmitter responsible for learning, memory, cognition and maintaining consciousness. In addition, AChE forms a complex with Aβ and changes the conformation of Aβ, therefore promotes the aggregation of Aβ. AChE inhibitor could inhibit the activity of AChE, but cannot stop the formation of AChE-Aβ. Therefore, AChE degradation by a small molecule becomes a new strategy for treating AD. Here, we designed and synthesized a series of multifunctional molecules which contained AChE-recognition moieties and E3 ligase-binding moieties to degrade the AChE, and then simultaneously improve the level of Ach and decrease the aggregation of Aβ. Among them, compound TKL-001, which could almost degrade all the AChE protein at 200μM, had the highest activity of inducing AChE degradation by increasing its poly-ubiquitination. Further modification of TKL-001 is ongoing." @default.
- W2896172637 created "2018-10-26" @default.
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- W2896172637 date "2018-07-01" @default.
- W2896172637 modified "2023-10-16" @default.
- W2896172637 title "P4‐212: NEW STRATEGY FOR TREATING AD: SPECIFIC DEGRADATION OF ACHE BY A SMALL MOLECULE" @default.
- W2896172637 doi "https://doi.org/10.1016/j.jalz.2018.07.033" @default.
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