| Autor: |
Lin, Yih‐Shyan, Tempest, Paul, Jang, Ming‐Kuei, Tai, Chin‐Yin, Wu, Meng‐Fang, Li, Chung‐Lin, Ma, Haou‐Tzong, Lai, Yen‐Ting |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Jun2023 Supplement 1, Vol. 19, p1-1, 1p |
| Abstrakt: |
Background: The hallmark of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), is an accumulation of protein aggregates, which lead to neurotoxicity and dysfunction. Small molecule therapeutics that can remove pathological aggregates are highly desired for both diseases. Method: Our small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, is selectively coupled with agents designed to hijack cellular quality‐control systems which facilitate aggregation clearance. We have developed a screening funnel to interrogate the ability of our small molecules to affect clearance of protein aggregates. Result: Therapeutic compounds developed have been shown to bind to intracellular tau aggregates in fluorescence assays. Furthermore, we have identified compounds that show proteosome dependent elimination of aSyn aggregates in the ReNcell VM neuronal model. PK studies show that these compounds can cross the BBB. In vivo studies with rTg4510 mice show that a single dose of our degraders can affect reduction of tau protein. Conclusion: APRINOIA's small molecule discovery platform has produced lead compounds capable of degrading protein aggregates in cellular assays and in vivo models. Further development is ongoing. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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