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Multiparameter optimization of new phenothiazines for proteasome activation

Award Number: R21AG061306
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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Multiparameter optimization of new phenothiazines for proteasome activation - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	2	9/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $220,149 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	2	10/29/2020	NON-COMPETING CONTINUATION	$220,149
														Subtotal = $220,149

Issue Date FY: 2020 ( Subtotal = $181,586 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Aging Research	000	1	1/10/2020	NEW	$181,586
														Subtotal = $181,586

Grand Total All Awards = $401,735

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Multiparameter optimization of new phenothiazines for proteasome activation

Award Number: R21AG061306

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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