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.

Public Health Relevance

Accumulation of intrinsically disordered proteins such as ?-synculein and tau result in harmful signaling and aggregation, which is seen in many neurodegenerative diseases. Reduction of their accumulation by 20S proteasome activation represents a new paradigm in drug discovery but the translational exploration of this therapeutic strategy has been limited due to the lack of suitable small molecule leads. In this work, we will use multiparameter optimization focused on both potency and physicochemical properties to generate the first 20S activator within CNS chemical space suitable for in vivo exploration of this new therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG061306-01
Application #
9647746
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Martin, Zane
Project Start
2020-01-15
Project End
2021-11-30
Budget Start
2020-01-15
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824